Pyrazolylaminopyridine derivatives useful as kinase inhibitors

ABSTRACT

This invention relates to novel compounds having the Formula (I) to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment for cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Stage under 35 U.S.C §371 ofInternational Application No. PCT/GB2006/000334 (filed Feb. 1, 2006)which claims priority under 35 U.S.C. §119(e) to U.S. ProvisionalApplication No. 60/650,053 filed on Feb. 4, 2005; to U.S. ProvisionalApplication No. 60/653,329, filed on Feb. 16, 2005; and to U.S.Provisional Application No. 60/721,633, filed on Sep. 29, 2005.

FIELD OF THE INVENTION

The present invention relates to novel pyrazole derivatives, theirpharmaceutical compositions and methods of use. In addition, the presentinvention relates to therapeutic methods for the treatment andprevention of cancers and to the use of these pyrazole derivatives inthe manufacture of medicaments for use in the treatment and preventionof cancers.

BACKGROUND OF THE INVENTION

Receptor tyrosine kinases (RTK's) are a sub-family of protein kinasesthat play a critical role in cell signalling and are involved in avariety of cancer related processes including cell proliferation,survival, angiogenesis and metastasis. Currently up to 100 differentRTK's including tropomyosin-related kinases (Trk's) have beenidentified.

Trk's are the high affinity receptors activated by a group of solublegrowth factors called neurotrophins (NT). The Trk receptor family hasthree members—TrkA, TrkB and TrkC. Among the NTs there are (i) nervegrowth factor (NGF) which activates TrkA, (ii) brain-derived growthfactor (BDNF) and NT-4/5 which activate TrkB and (iii) NT3 whichactivates TrkC. Each Trk receptor contains an extra-cellular domain(ligand binding), a trans-membrane region and an intra-cellular domain(including kinase domain). Upon binding of the ligand, the kinasecatalyzes auto-phosphorylation and triggers downstream signaltransduction pathways.

Trk's are widely expressed in neuronal tissue during its developmentwhere Trk's are critical for the maintenance and survival of thesecells. A post-embryonic role for the Trk/neurotrophin axis (or pathway),however, remains in question. There are reports showing that Trk's playimportant role in both development and function of the nervous system(Patapoutian, A. et al Current Opinion in Neurobiology, 2001, 11,272-280).

In the past decade, a considerable number of literature documentationslinking Trk signalling with cancer have published. For example, whileTrk's are expressed at low levels outside the nervous system in theadult, Trk expression is increased in late stage prostate cancers. Bothnormal prostate tissue and androgen-dependent prostate tumours expresslow levels of Trk A and undetectable levels of Trk B and C. However, allisoforms of Trk receptors as well as their cognate ligands areup-regulated in late stage, androgen-independent prostate cancer. Thereis additional evidence that these late stage prostate cancer cellsbecome dependent on the Trk/neurotrophin axis for their survival.Therefore, Trk inhibitors may yield a class of apoptosis-inducing agentsspecific for androgen-independent prostate cancer (Weeraratna, A. T. etal The Prostate, 2000, 45, I40-I48).

Furthermore, very recent literature also shows that over-expression,activation, amplification and/or mutation of Trk's are associated withsecretory breast carcinoma (Cancer Cell, 2002, 2, 367-376), colorectalcancer (Bardelli et al Science, 2003, 300, 949-949) and ovarian cancer(Davidson, B. et al Clinical Cancer Research, 2003, 9, 2248-2259).

There are a few reports of selective Trk tyrosine kinase inhibitors.Cephalon described CEP-751, CEP-701 (George, D. et al Cancer Research,1999, 59, 2395-2341) and other indolocarbazole analogues (WO0114380) asTrk inhibitors. It was shown that CEP-701 and/or CEP751, when combinedwith surgically or chemically induced androgen ablation, offered betterefficacy compared with mono-therapy alone. GlaxoSmithKline disclosedcertain oxindole compounds as Trk A inhibitors in WO0220479 andWO0220513. Recently, Japan Tobacco reported pyrazolyl condensed cycliccompounds as Trk inhibitors (JP2003231687A).

In addition to the above, Vertex Pharmaceuticals have described pyrazolecompounds as inhibitors of GSK3, Aurora, etc. in WO0250065, WO0262789,WO03027111 and WO200437814; and AstraZeneca have reported pyrazolecompounds as inhibitors against IGF-1 receptor kinase (WO0348133).

SUMMARY OF THE INVENTION

In accordance with the present invention, the applicants have herebydiscovered novel pyrazole compounds, or pharmaceutically acceptablesalts thereof, which possess Trk kinase inhibitory activity and areaccordingly useful for their anti-proliferation and/or proapoptotic(such as anti-cancer) activity and in methods of treatment of the humanor animal body. The invention also relates to processes for themanufacture of said pyrazole compounds, or pharmaceutically acceptablesalts thereof, to pharmaceutical compositions containing them and totheir use in the manufacture of medicaments for use in the production ofan anti-proliferation and/or proapoptotic effect in warm-blooded animalssuch as man.

Also in accordance with the present invention the applicants providemethods of using such pyrazole compounds, or pharmaceutically acceptablesalts thereof, in the treatment of cancer.

The properties of the compounds claimed in this invention are expectedto be of value in the treatment of disease states associated with cellproliferation such as cancers (solid tumors and leukemia),fibroproliferative and differentiative disorders, psoriasis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation.

Furthermore, the compounds, or pharmaceutically acceptable saltsthereof, of the invention are expected to be of value in the treatmentor prophylaxis of cancers selected from congenital fibrosarcoma,mesoblastic nephroma, mesothelioma, acute myeloblastic leukemia, acutelymphocytic leukemia, multiple myeloma, melanoma, oesophageal cancer,myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma,neuroblastoma, Kaposi sarcoma, ovarian cancer, breast cancer includingsecretory breast cancer, colorectal cancer, prostate cancer includinghormone refractory prostate cancer, bladder cancer, melanoma, lungcancer—non small cell lung cancer (NSCLC), and small cell lung cancer(SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma,thyroid cancer including papillary thyroid cancer, mesothelioma andleukaemia; particularly ovarian cancer, breast cancer, colorectalcancer, prostate cancer and lung cancer—NSCLC and SCLC; moreparticularly prostate cancer; and more particularly hormone refractoryprostate cancer.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides a compound of formula (I):

wherein:

R¹ and R² are independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂-amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂-carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R¹ and R²independently of each other may be optionally substituted on carbon byone or more R⁶; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected from R⁷;

one of X¹, X², X³ and X⁴ is ═N—, the other three are independentlyselected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—;

R³ is hydrogen or optionally substituted C₁₋₆alkyl; wherein saidoptional substituents are selected from one or more R¹¹;

R⁴ and R³⁴ are independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R⁴ and R³⁴may be independently optionally substituted on carbon by one or moreR¹²; and wherein if said heterocyclyl contains an —NH— moiety thatnitrogen may be optionally substituted by a group selected from R¹³;

A is a direct bond or C₁₋₂alkylene; wherein said C₁₋₂alkylene may beoptionally substituted by one or more R¹⁴;

Ring C is carbocyclyl or heterocyclyl; wherein if said heterocyclylcontains an —NH— moiety that nitrogen may be optionally substituted by agroup selected from R¹⁵;

R⁵ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl-R³⁷— orheterocyclyl-R³⁸—; wherein R⁵ may be optionally substituted on carbon byone or more R¹⁶; and wherein if said heterocyclyl contains an —NH—moiety that nitrogen may be optionally substituted by a group selectedfrom R¹⁷;

n is 0, 1, 2 or 3; wherein the values of R⁵ may be the same ordifferent;

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halo, nitro,cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R²⁵— or heterocyclyl-R²⁶—; whereinR⁸, R⁹ and R¹⁰ independently of each other may be optionally substitutedon carbon by one or more R¹⁸; and wherein if said heterocyclyl containsan —NH— moiety that nitrogen may be optionally substituted by a groupselected from R¹⁹;

R⁶, R¹¹, R¹², R¹⁴, R¹⁶ and R¹⁸ are independently selected from halo,nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R²⁷— or heterocyclyl-R²⁸—; whereinR⁶, R¹¹, R¹², R¹⁴, R¹⁶ and R¹⁸ independently of each other may beoptionally substituted on carbon by one or more R²⁰; and wherein if saidheterocyclyl contains an —NH— moiety that nitrogen may be optionallysubstituted by a group selected from R²¹;

R⁷, R¹³, R¹⁵, R¹⁷, R¹⁹ and R²¹ are independently selected fromC₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl,carbamoyl, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R⁷, R¹³, R¹⁵,R¹⁷, R¹⁹ and R²¹ independently of each other may be optionallysubstituted on carbon by on or more R²²;

R²⁰ and R²² are independently selected from halo, nitro, cyano, hydroxy,trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, C₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino,carbocyclyl-R³⁵— or heterocyclyl-R³⁶—; wherein R²⁰ and R²² independentlyof each other may be optionally substituted on carbon by one or moreR²³; and wherein if said heterocyclyl contains an —NH— moiety thatnitrogen may be optionally substituted by a group selected from R²⁴;

R²⁵, R²⁶, R²⁷, R²⁸, R³⁵, R³⁶, R³⁷ and R³⁸ are independently selectedfrom a direct bond, —O—, —N(R²⁹)—, —C(O)—, —N(R³⁰)C(O)—, —C(O)N(R³¹)—,—S(O)_(s)—, —NH═CH—, —SO₂N(R³²)— or —N(R³³)SO₂—; wherein R²⁹, R³⁰, R³¹,R³² and R³³ are independently selected from hydrogen or C₁₋₆alkyl and sis 0-2;

R²³ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl,N-methyl-N-ethylsulphamoyl or phenyl; and

R²⁴ is selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl;

or a pharmaceutically acceptable salt thereof.

According to a further feature of the present invention there isprovided a compound of formula (I) which is a compound of formula (Ia):

wherein:

R¹ and R² are independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R¹ and R²independently of each other may be optionally substituted on carbon byone or more R⁶; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected from R⁷;

one of X¹, X², X³ and X⁴ is ═N—, the other three are independentlyselected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—;

R³ is hydrogen or optionally substituted C₁₋₆alkyl; wherein saidoptional substituents are selected from one or more R¹¹;

R⁴ is selected from hydrogen, halo, nitro, cyano, hydroxy,trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R⁴ may beoptionally substituted on carbon by one or more R¹²; and wherein if saidheterocyclyl contains an —NH— moiety that nitrogen may be optionallysubstituted by a group selected from R¹³;

A is a direct bond or C₁₋₂alkylene; wherein said C₁₋₂alkylene may beoptionally substituted by one or more R¹⁴;

Ring C is carbocyclyl or heterocyclyl; wherein if said heterocyclylcontains an —NH— moiety that nitrogen may be optionally substituted by agroup selected from R¹⁵;

R⁵ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl orheterocyclyl; wherein R⁵ may be optionally substituted on carbon by oneor more R¹⁶; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected fromR¹⁷;

n is 0, 1, 2 or 3; wherein the values of R⁵ may be the same ordifferent;

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halo, nitro,cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R²⁵— or heterocyclyl-R²⁶—; whereinR⁸, R⁹ and R¹⁰ independently of each other may be optionally substitutedon carbon by one or more R¹⁸; and wherein if said heterocyclyl containsan —NH— moiety that nitrogen may be optionally substituted by a groupselected from R¹⁹;

R⁶, R¹¹, R¹², R¹⁴, R¹⁶ and R¹⁸ are independently selected from halo,nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R²⁷— or heterocyclyl-R²⁸—; whereinR⁶, R¹¹, R¹², R¹⁴, R¹⁶ and R¹⁸ independently of each other may beoptionally substituted on carbon by one or more R²⁰; and wherein if saidheterocyclyl contains an —NH— moiety that nitrogen may be optionallysubstituted by a group selected from R²¹;

R⁷, R¹³, R¹⁵, R¹⁷, R¹⁹ and R²¹ are independently selected fromC₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl,carbamoyl, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R⁷, R¹³, R¹⁵,R¹⁷, R¹⁹ and R²¹ independently of each other may be optionallysubstituted on carbon by on or more R²²;

R²⁰ and R²² are independently selected from halo, nitro, cyano, hydroxy,trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R²⁰ andR²² independently of each other may be optionally substituted on carbonby one or more R²³; and wherein if said heterocyclyl contains an —NH—moiety that nitrogen may be optionally substituted by a group selectedfrom R²⁴;

R²⁵, R²⁶, R²⁷ and R²⁸ are independently selected from a direct bond,—O—, —N(R²⁹)—, —C(O)—, —N(R³⁰)C(O)—, —C(O)N(R³¹)—, —S(O)_(s)—,—SO₂N(R³²)— or —N(R³³)SO₂—; wherein R²⁹, R³⁰, R³¹, R³² and R³³ areindependently selected from hydrogen or C₁₋₆alkyl and s is 0-2;

R²³ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl orN-methyl-N-ethylsulphamoyl; and

R²⁴ is selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl;

or a pharmaceutically acceptable salt thereof.

Accordingly to a further feature of the present invention there isprovided a compound of formula (I) wherein:

R¹ and R² are independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R¹ and R²independently of each other may be optionally substituted on carbon byone or more R⁶; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected from R⁷;

one of X¹, X², X³ and X⁴ is ═N—, the other three are independentlyselected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—;

R³ is hydrogen or optionally substituted C₁₋₆alkyl; wherein saidoptional substituents are selected from one or more R¹¹;

R⁴ and R³⁴ are independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R⁴ and R³⁴may be independently optionally substituted on carbon by one or moreR¹²; and wherein if said heterocyclyl contains an —NH— moiety thatnitrogen may be optionally substituted by a group selected from R¹³;

A is a direct bond or C₁₋₂alkylene; wherein said C₁₋₂alkylene may beoptionally substituted by one or more R¹⁴;

Ring C is carbocyclyl or heterocyclyl; wherein if said heterocyclylcontains an —NH— moiety that nitrogen may be optionally substituted by agroup selected from R¹⁵;

R⁵ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl orheterocyclyl; wherein R⁵ may be optionally substituted on carbon by oneor more R¹⁶; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected fromR¹⁷;

n is 0, 1, 2 or 3; wherein the values of R⁵ may be the same ordifferent;

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halo, nitro,cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R²⁵— or heterocyclyl-R²⁶—; whereinR⁸, R⁹ and R¹⁰ independently of each other may be optionally substitutedon carbon by one or more R¹⁸; and wherein if said heterocyclyl containsan —NH— moiety that nitrogen may be optionally substituted by a groupselected from R¹⁹;

R⁶, R¹¹, R¹², R¹⁴, R¹⁶ and R¹⁸ are independently selected from halo,nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R²⁷— or heterocyclyl-R²⁸—; whereinR⁶, R¹¹, R¹², R¹⁴, R¹⁶ and R¹⁸ independently of each other may beoptionally substituted on carbon by one or more R²⁰; and wherein if saidheterocyclyl contains an —NH— moiety that nitrogen may be optionallysubstituted by a group selected from R²¹;

R⁷, R¹³, R¹⁵, R¹⁷, R¹⁹ and R²¹ are independently selected fromC₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl,carbamoyl, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R⁷, R³, R¹⁵,R¹⁷, R¹⁹ and R²¹ independently of each other may be optionallysubstituted on carbon by on or more R²²;

R²⁰ and R²² are independently selected from halo, nitro, cyano, hydroxy,trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R²⁰ andR²² independently of each other may be optionally substituted on carbonby one or more R²³; and wherein if said heterocyclyl contains an —NH—moiety that nitrogen may be optionally substituted by a group selectedfrom R²⁴;

R²⁵, R²⁶, R²⁷ and R²⁸ are independently selected from a direct bond,—O—, —N(R²⁹)—, —C(O)—, —N(R³⁰)C(O)—, —C(O)N(R³¹)—, —S(O)_(s)—,—SO₂N(R³²)— or —N(R³³)SO₂—; wherein R²⁹, R³⁰, R³¹, R³² and R³³ areindependently selected from hydrogen or C₁₋₆alkyl and s is 0-2;

R²³ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl orN-methyl-N-ethylsulphamoyl; and

R²⁴ is selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl;

or a pharmaceutically acceptable salt thereof.

According to a further feature of the invention there is provided acompound of formula (I) wherein:

R¹ and R² are independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R¹ and R²independently of each other may be optionally substituted on carbon byone or more R⁶; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected from R⁷;

one of X¹, X², X³ and X⁴ is ═N—, the other three are independentlyselected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—;

R³ is hydrogen or optionally substituted C₁₋₆alkyl; wherein saidoptional substituents are selected from one or more R¹¹;

R⁴ and R³⁴ are independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R⁴ and R³⁴may be independently optionally substituted on carbon by one or moreR¹²; and wherein if said heterocyclyl contains an —NH— moiety thatnitrogen may be optionally substituted by a group selected from R¹³;

A is a direct bond or C₁₋₂alkylene; wherein said C₁₋₂alkylene may beoptionally substituted by one or more R¹⁴;

Ring C is carbocyclyl or heterocyclyl; wherein if said heterocyclylcontains an —NH— moiety that nitrogen may be optionally substituted by agroup selected from R¹⁵;

R⁵ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl orheterocyclyl; wherein R⁵ may be optionally substituted on carbon by oneor more R¹⁶; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected fromR¹⁷;

n is 0, 1, 2 or 3; wherein the values of R⁵ may be the same ordifferent;

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halo, nitro,cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R²⁵— or heterocyclyl-R²⁶—; whereinR⁸, R⁹ and R¹⁰ independently of each other may be optionally substitutedon carbon by one or more R¹⁸; and wherein if said heterocyclyl containsan —NH— moiety that nitrogen may be optionally substituted by a groupselected from R¹⁹;

R⁶, R¹¹, R¹², R¹⁴, R¹⁶ and R¹⁸ are independently selected from halo,nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R²⁷— or heterocyclyl-R²⁸—; whereinR⁶, R¹¹, R¹², R¹⁴, R¹⁶ and R¹⁸ independently of each other may beoptionally substituted on carbon by one or more R²⁰; and wherein if saidheterocyclyl contains an —NH— moiety that nitrogen may be optionallysubstituted by a group selected from R²¹;

R⁷, R¹³, R¹⁵, R¹⁷, R¹⁹ and R²¹ are independently selected fromC₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl,carbamoyl, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R⁷, R¹³, R¹⁵,R⁷, R¹⁹ and R²¹ independently of each other may be optionallysubstituted on carbon by on or more R²²;

R²⁰ and R²² are independently selected from halo, nitro, cyano, hydroxy,trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, C₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino,carbocyclyl-R³⁵— or heterocyclyl-R³⁶—; wherein R²⁰ and R²² independentlyof each other may be optionally substituted on carbon by one or moreR²³; and wherein if said heterocyclyl contains an —NH— moiety thatnitrogen may be optionally substituted by a group selected from R²⁴;

R²⁵, R²⁶, R²⁷, R²⁸, R³⁵ and R³⁶ are independently selected from a directbond, —O—, —N(R²⁹)—, —C(O)—, —N(R³⁰)C(O)—, —C(O)N(R³¹)—, —S(O)_(s)—,—NH═CH—, —SO₂N(R³²)— or —N(R³³)SO₂—; wherein R²⁹, R³⁰, R³¹, R³² and R³³are independently selected from hydrogen or C₁₋₆alkyl and s is 0-2;

R²³ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl,N-methyl-N-ethylsulphamoyl or phenyl; and

R²⁴ is selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl;

or a pharmaceutically acceptable salt thereof.

Particular values of the variable groups contained in formula (I) are asfollows. Such values may be used, where appropriate, with any of thedefinitions, claims or embodiments defined hereinbefore or hereinafter.

R¹ is C₁₋₆alkoxy or carbocyclyl.

R¹ is C₁₋₆alkyl, C₁₋₆alkoxy and cyclopropyl.

R¹ is isopropoxy or cyclopropyl.

R¹ is C₁₋₆alkoxy.

R¹ is cyclopropyl.

R¹ is isopropoxy.

R¹ is methyl, t-butyl, isopropoxy or cyclopropyl.

R¹ is hydrogen.

R¹ and R² are independently selected from hydrogen, C₁₋₆alkoxy andcarbocyclyl.

R¹ and R² are independently selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy and carbocyclyl.

R¹ and R² are independently selected from hydrogen, C₁₋₆alkoxy andcyclopropyl.

R¹ and R² are independently selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy and cyclopropyl.

R¹ and R² are independently selected from hydrogen, isopropoxy andcyclopropyl.

R¹ and R² are independently selected from hydrogen, methyl, t-butyl,isopropoxy and cyclopropyl.

R¹ is C₁₋₆alkoxy or carbocyclyl and R² is hydrogen.

R¹ is C₁₋₆alkyl, C₁₋₆alkoxy or carbocyclyl and R² is hydrogen.

R¹ is C₁₋₆alkoxy and cyclopropyl and R² is hydrogen.

R¹ is C₁₋₆alkyl, C₁₋₆alkoxy and cyclopropyl and R² is hydrogen.

R¹ is C₁₋₆alkoxy and R² is hydrogen.

R¹ is isopropoxy and R² is hydrogen.

R¹ is cyclopropyl and R² is hydrogen.

R¹ is isopropoxy or cyclopropyl and R² is hydrogen.

R¹ is methyl, t-butyl, isopropoxy or cyclopropyl and R² is hydrogen.

X¹ is ═N—, X² is ═CR⁸—, X³ is ═CR⁹— and X⁴ is ═CR¹⁰—.

X² is ═N—, X¹ is ═CR⁸—, X³ is ═CR⁹— and X⁴ is ═CR¹⁰—.

X³ is ═N—, X² is ═CR⁸—, X¹ is ═CR⁹— and X⁴ is ═CR¹⁰—.

X⁴ is ═N—, X² is ═CR⁸—, X³ is ═CR⁹— and X⁴ is ═CR¹⁰—.

X³ or X⁴ is —N—, X¹ and X² and the other of X³ and X⁴ are independentlyselected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—.

R³ is hydrogen.

R³ is optionally substituted C₁₋₆alkyl; wherein said optionalsubstituents are selected from one or more R¹¹.

R⁴ is not hydrogen.

R⁴ is selected from hydrogen or C₁₋₆alkyl; wherein R⁴ may be optionallysubstituted on carbon by one or more R¹²; wherein R¹² is selected fromhydroxy.

R⁴ is selected from hydrogen or C₁₋₆alkyl; wherein R⁴ may be optionallysubstituted on carbon by one or more R¹²; wherein R¹² is selected fromhydroxy and R³⁴ is hydrogen.

R⁴ and R³⁴ are independently selected from hydrogen or C₁₋₆alkyl;wherein R⁴ and R³⁴ may be independently optionally substituted on carbonby one or more R¹²; wherein R¹² is selected from hydroxy.

R⁴ is selected from hydrogen or methyl; wherein R⁴ may be optionallysubstituted on carbon by one or more R¹²; wherein R¹² is selected fromhydroxy.

R⁴ is selected from hydrogen or methyl; wherein R⁴ may be optionallysubstituted on carbon by one or more R¹²; wherein R¹² is selected fromhydroxy and R³⁴ is hydrogen.

R⁴ and R³⁴ are independently selected from hydrogen or methyl; whereinR⁴ and R³⁴ may be independently optionally substituted on carbon by oneor more R¹²; wherein R¹² is selected from hydroxy.

R⁴ is selected from hydrogen, methyl or hydroxymethyl.

R⁴ is selected from hydrogen, methyl or hydroxymethyl and R³⁴ ishydrogen.

R⁴ and R³⁴ are independently selected from hydrogen, methyl orhydroxymethyl.

R³⁴ is selected from hydrogen.

R³⁴ is selected from hydrogen or hydroxymethyl.

R⁴ is selected from methyl or hydroxymethyl.

R⁴ is selected from methyl or hydroxymethyl and R³⁴ is hydrogen.

R⁴ is selected from methyl and R³⁴ is hydrogen.

R⁴ is selected from hydroxymethyl and R³⁴ is hydrogen.

A is a direct bond.

A is C₁₋₂alkylene; wherein said C₁₋₂alkylene may be optionallysubstituted by one or more R¹⁴.

Ring C is carbocyclyl.

Ring C is or heterocyclyl; wherein if said heterocyclyl contains an —NH—moiety that nitrogen may be optionally substituted by a group selectedfrom R¹⁵;

Ring C is carbocyclyl or heterocyclyl.

Ring C is phenyl, pyridyl or pyrimidinyl.

Ring C is phenyl, pyrid-2-yl, pyrid-3-yl or pyrimidin-2-yl.

Ring C is phenyl.

Ring C is pyridyl.

Ring C is pyrid-2-yl.

R⁵ is selected from halo, C₁₋₆alkanoylamino, C₁₋₆alkylsulphonylamino orcarbocyclyl-R³⁷—; wherein

R³⁷ is —C(O)N(R³¹)—; wherein R³¹ is hydrogen.

R⁵ is halo.

R⁵ is selected from fluoro, acetylamino, mesylamino or cyclopropyl-R³⁷—;wherein R³⁷ is —C(O)N(R³¹)—; wherein R³¹ is hydrogen.

R⁵ is fluoro.

R⁵ is selected from fluoro, acetylamino, mesylamino orcyclopropylcarbonylamino.

n is 0.

n is 1.

n is 1 or 2; wherein the values of R⁵ may be the same or different.

n is 2; wherein the values of R⁵ may be the same or different.

n is 3; wherein the values of R⁵ may be the same or different.

Ring C and (R⁵)_(n) together form 4-fluorophenyl; wherein the fluorogroup is para to the A group of formula (I).

Ring C and (R⁵)_(n) together form 4-fluorophenyl, 5-fluoropyrid-2-yl,3,5-difluoropyrid-2-yl, 5-fluoropyrimidin-2-yl,4-fluoro-3-mesylaminophenyl, 6-fluoropyrid-3-yl,4-fluoro-3-acetylaminophenyl and 4-fluoro-3-cyclopropylcabonylamino.

Ring C and (R⁵)_(n) together form 5-fluoropyrid-2-yl; wherein the fluorogroup is para to the A group of formula (I).

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halo, nitro,cyano, amino, carboxy, carbamoyl, C₁₋₆alkyl, C₁₋₆alkanoyl,N—(C₁₋₆alkyl)amino or carbocyclyl-R²⁵—; wherein R⁸, R⁹ and R¹⁰independently of each other may be optionally substituted on carbon byone or more R¹⁸;

R¹⁸ is selected from hydroxy, amino, N—(C₁₋₆alkyl)amino,C₁₋₆alkanoylamino, C₁₋₆alkylsulphonylamino, carbocyclyl-R²⁷— orheterocyclyl-R²⁸—; wherein R¹⁸ may be optionally substituted on carbonby one or more R²⁰; and wherein if said heterocyclyl contains an —N—H—moiety that nitrogen may be optionally substituted by a group selectedfrom R²¹;

R²⁰ is selected from halo, amino, C₁₋₆alkyl, N,N—(C₁₋₆alkyl)₂amino,C₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino, carbocyclyl-R³⁵— orheterocyclyl-R³⁶—; wherein R²⁰ may be optionally substituted on carbonby one or more R²³;

R²¹ is selected from C₁₋₆alkylsulphonyl;

R²³ is dimethylamino or phenyl; and

R²⁷, R²⁸, R³⁵ and R³⁶ are independently selected from a direct bond,—C(O)N(R³¹)—, —NH═CH— or —SO₂N(R³²)—; wherein R³¹ and R³² areindependently selected from hydrogen or C₁₋₆alkyl.

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halo, nitro,cyano, amino, carbamoyl and C₁₋₆alkyl; wherein R⁸, R⁹ and R¹⁰independently of each other may be optionally substituted on carbon byone or more R¹⁸; wherein

R¹⁸ is selected from amino, C₁₋₆alkanoylamino, C₁₋₆alkylsulphonylaminoor heterocyclyl-R²⁸—; wherein R¹⁸ may be optionally substituted oncarbon by one or more R²⁰;

R²⁰ is amino; and

R²⁸ is —C(O)N(R³¹)—; wherein R³¹ is hydrogen.

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, fluoro, chloro,iodo, nitro, cyano, amino, carboxy, carbamoyl, methyl, isopropyl,formyl, methylamino, isopropylamino or cyclopropyl-R²⁵—; wherein R⁸, R⁹and R¹⁰ independently of each other may be optionally substituted oncarbon by one or more R¹⁸;

R¹⁸ is selected from hydroxy, amino, methylamino, acetylamino,propionylamino, 3-methylbutanoylamino, mesylamino, cyclopropyl-R²⁷—,phenyl-R²⁷—, tetrahydrofuran-2-yl-R²⁸—, furan-2-yl-R²⁸—,pyrrol-2-yl-R²⁸—, isoxaxol-5-yl-R²⁸—, isoxaxol-4-yl-R²⁸—,piperidin-4-yl-R²⁸—, thien-2-yl-R²⁸—, pyrid-3-yl-R²⁸—, pyrid-4-yl-R²⁸—,tetrahydro-2H-thiopyran-4-yl-R²⁸—, morpholino-R²⁸— or2-oxopyrrolidin-5-yl-R²⁸—; wherein R¹⁸ may be optionally substituted oncarbon by one or more R²⁰; and wherein if said heterocyclyl contains an—NH— moiety that nitrogen may be optionally substituted by a groupselected from R²¹;

R²⁰ is selected from fluoro, amino, methyl, dimethylamino,N-(isopropyl)-N-(mesyl)amino, N-(ethyl)-N-(mesyl)amino, phenyl-R³⁵—,thien-2-yl-R³⁶—, thien-3-yl-R³⁶—, pyrid-3-yl-R³⁶— or morpholino-R³⁶—;wherein R²⁰ may be optionally substituted on carbon by one or more R²³;

R²¹ is selected from mesyl;

R²³ is dimethylamino or phenyl; and

R²⁷, R²⁸, R³⁵ and R³⁶ are independently selected from a direct bond,—C(O)N(R³)—, —NH═CH— or —SO₂N(R³²)—; wherein R³¹ and R³² areindependently selected from hydrogen or methyl.

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, fluoro, chloro,nitro, cyano, amino, carboxy, carbamoyl, methyl, isopropyl, formyl,methylamino, isopropylamino or cyclopropyl-R²⁵—; wherein R⁸, R⁹ and R¹⁰independently of each other may be optionally substituted on carbon byone or more R¹⁸;

R¹⁸ is selected from hydroxy, amino, methylamino, acetylamino,propionylamino, 3-methylbutanoylamino, mesylamino, cyclopropyl-R²⁷—,phenyl-R²⁷—, tetrahydrofuran-2-yl-R²⁸—, furan-2-yl-R²⁸—,pyrrol-2-yl-R²⁸—, isoxaxol-5-yl-R²⁸—, isoxaxol-4-yl-R²⁸—,piperidin-4-yl-R²⁸—, thien-2-yl-R²⁸—, pyrid-3-yl-R²⁸—, pyrid-4-yl-R²⁸—,tetrahydro-2H-thiopyran-4-yl-R²⁸—, morpholino-R²⁸— or2-oxopyrrolidin-5-yl-R²⁸—; wherein R¹⁸ may be optionally substituted oncarbon by one or more R²⁰; and wherein if said heterocyclyl contains an—NH— moiety that nitrogen may be optionally substituted by a groupselected from R²¹;

R²⁰ is selected from fluoro, amino, methyl, dimethylamino,N-(isopropyl)-N-(mesyl)amino, N-(ethyl)-N-(mesyl)amino, phenyl-R³⁵—,thien-2-yl-R³⁶—, thien-3-yl-R³⁶—, pyrid-3-yl-R³⁶— or morpholino-R³⁶—;wherein R²⁰ may be optionally substituted on carbon by one or more R²³;

R²¹ is selected from mesyl;

R²³ is dimethylamino or phenyl; and

R²⁷, R²⁸, R³⁵ and R³⁶ are independently selected from a direct bond,—C(O)N(R³¹)—, —NH═CH— or —SO₂N(R³²)—; wherein R³¹ and R³² areindependently selected from hydrogen or methyl.

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, fluoro, chloro,nitro, cyano, amino, carbamoyl and methyl; wherein R⁸, R⁹ and R¹⁰independently of each other may be optionally substituted on carbon byone or more R¹⁸; wherein

R¹⁸ is selected from amino, acetylamino, mesylamino or2-oxopyrrolidin-5-yl-R²⁸—; wherein R¹⁸ may be optionally substituted oncarbon by one or more R²⁰;

R²⁰ is amino; and

R²⁸ is —C(O)N(R³¹)—; wherein R³¹ is hydrogen.

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, fluoro, chloro,iodo, nitro, cyano, amino, carboxy, carbamoyl, formyl, methylamino,hydroxymethyl, acetylaminomethyl, (2-aminoacetyl)aminomethyl,(2-morpholinoacetyl)aminomethyl,(R)-2-oxopyrrolidin-5-yl-carbonylaminomethyl,(S)-2-oxopyrrolidin-5-yl-carbonylaminomethyl,(R,S)-2-oxopyrrolidin-5-yl-carbonylaminomethyl,isoxaxol-5-yl-carbonylaminomethyl, mesylaminomethyl, morpholinomethyl,benzoylaminomethyl, pyrid-3-yl-carbonylaminomethyl,6-dimethylaminopyrid-3-yl-carbonylaminomethyl,6-morpholinopyrid-3-yl-carbonylaminomethyl,pyrid-4-yl-carbonylaminomethyl,5-methylisoxaxol-4-yl-carbonylaminomethyl,thien-2-yl-carbonylaminomethyl,4-dimethylaminobenzylcarbonylaminomethyl,2-(N-(isopropyl)-N-(mesyl)amino)acetylaminomethyl,2-(N-(phenethyl)-N-(mesyl)amino)acetylaminomethyl,1-mesylpiperidin-1-ylcarbonylaminomethyl,2-(pyrid-3-yl)acetylaminomethyl,tetrahydro-2H-thiopyran-4-yl-carbonylaminomethyl,2-(thien-2-yl)acetylcarbonylaminomethyl,2-(thien-3-yl)acetylcarbonylaminomethyl, 3-phenylpropionylaminomethyl,2-(N-benzoyl-N-methylamino)acetylaminomethyl,4-dimethylaminobenzoylaminomethyl, phenylsulphonylaminomethyl,2-amino-3-methylbutanoylaminomethyl, cyclopropylcarbonylaminomethyl,pyrrol-2-yl-carbonylaminomethyl,tetrahydrofuran-2-yl-carbonylaminomethyl,furan-2-yl-carbonylaminomethyl, cyclopropylsulphonylaminomethyl,(cyclopropylimino)methyl, methylaminomethyl, trifluoromesylaminomethyl,isopropyl, isopropylamino or methylamino.

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, fluoro, chloro,nitro, cyano, amino, carboxy, carbamoyl, formyl, methylamino,hydroxymethyl, acetylaminomethyl, (2-aminoacetyl)aminomethyl,(2-morpholinoacetyl)aminomethyl,(R)-2-oxopyrrolidin-5-yl-carbonylaminomethyl,(S)-2-oxopyrrolidin-5-yl-carbonylaminomethyl,(R,S)-2-oxopyrrolidin-5-yl-carbonylaminomethyl,isoxaxol-5-yl-carbonylaminomethyl, mesylaminomethyl, morpholinomethyl,benzoylaminomethyl, pyrid-3-yl-carbonylaminomethyl,6-dimethylaminopyrid-3-yl-carbonylaminomethyl,6-morpholinopyrid-3-yl-carbonylaminomethyl,pyrid-4-yl-carbonylaminomethyl,5-methylisoxaxol-4-yl-carbonylaminomethyl,thien-2-yl-carbonylaminomethyl,4-dimethylaminobenzylcarbonylaminomethyl,2-(N-(isopropyl)-N-(mesyl)amino)acetylaminomethyl,2-(N-(phenethyl)-N-(mesyl)amino)acetylaminomethyl,1-mesylpiperidin-1-ylcarbonylaminomethyl,2-(pyrid-3-yl)acetylaminomethyl,tetrahydro-2H-thiopyran-4-yl-carbonylaminomethyl,2-(thien-2-yl)acetylcarbonylaminomethyl,2-(thien-3-yl)acetylcarbonylaminomethyl, 3-phenylpropionylaminomethyl,2-(N-benzoyl-N-methylamino)acetylaminomethyl,4-dimethylaminobenzoylaminomethyl, phenylsulphonylaminomethyl,2-amino-3-methylbutanoylaminomethyl, cyclopropylcarbonylaminomethyl,pyrrol-2-yl-carbonylaminomethyl,tetrahydrofuran-2-yl-carbonylaminomethyl,furan-2-yl-carbonylaminomethyl, cyclopropylsulphonylaminomethyl,(cyclopropylimino)methyl, methylaminomethyl, trifluoromesylaminomethyl,isopropyl, isopropylamino or methylamino.

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, fluoro, chloro,nitro, cyano, amino, carbamoyl, aminomethyl, acetylaminomethyl,mesylaminomethyl, 2-oxopyrrolidin-5-ylcarbonylaminomethyl and(2-aminoacetyl)aminomethyl.

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, fluoro andcyano.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ and R² are independently selected from hydrogen, C₁₋₆alkoxy andcarbocyclyl;

X³ or X⁴ is ═N—, X¹ and X² and the other of X³ and X⁴ are independentlyselected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—;

R³ is hydrogen;

R⁴ is selected from hydrogen or C₁₋₆alkyl; wherein R⁴ may be optionallysubstituted on carbon by one or more R¹²;

R³⁴ is hydrogen;

A is a direct bond;

Ring C is carbocyclyl;

R⁵ is halo;

n is 1;

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halo, nitro,cyano, amino, carbamoyl and C₁₋₆alkyl; wherein R⁸, R⁹ and R¹⁰independently of each other may be optionally substituted on carbon byone or more R¹⁸;

R¹² is selected from hydroxy;

R¹⁸ is selected from amino, C₁₋₆alkanoylamino, C₁₋₆alkylsulphonylaminoor heterocyclyl-R²⁸—; wherein R¹⁸ may be optionally substituted oncarbon by one or more R²⁰;

R²⁰ is amino; and

R²⁸ is —C(O)N(R³¹)—; wherein R³¹ is hydrogen;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ and R² are independently selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy and carbocyclyl;

X³ or X⁴ is ═N—, X¹ and X² and the other of X³ and X⁴ are independentlyselected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—;

R³ is hydrogen;

R⁴ and R³⁴ are independently selected from hydrogen or C₁₋₆alkyl;wherein R⁴ and R³⁴ may be independently optionally substituted on carbonby one or more R¹²;

A is a direct bond;

Ring C is carbocyclyl;

R⁵ is halo;

n is 1;

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halo, nitro,cyano, amino, carbamoyl and C₁₋₆alkyl; wherein R⁸, R⁹ and R¹⁰independently of each other may be optionally substituted on carbon byone or more R¹⁸;

R¹² is selected from hydroxy;

R¹⁸ is selected from amino, C₁₋₆alkanoylamino, C₁₋₆alkylsulphonylaminoor heterocyclyl-R²⁸—; wherein R¹⁸ may be optionally substituted oncarbon by one or more R²⁰;

R²⁰ is amino; and

R²⁸ is —C(O)N(R³¹)—; wherein R³¹ is hydrogen;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ is C₁₋₆alkyl, C₁₋₆alkoxy or carbocyclyl;

R² is hydrogen;

X³ or X⁴ is ═N—, X¹ and X² and the other of X³ and X⁴ are independentlyselected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—;

R³ is hydrogen;

R⁴ and R³⁴ are independently selected from hydrogen or C₁₋₆alkyl;wherein R⁴ and R³⁴ may be independently optionally substituted on carbonby one or more R¹²; wherein R¹² is selected from hydroxy;

A is a direct bond;

Ring C is carbocyclyl;

R⁵ is halo;

n is 1;

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halo, nitro,cyano, amino, carboxy, carbamoyl, C₁₋₆alkyl, C₁₋₆alkanoyl,N—(C₁₋₆alkyl)amino or carbocyclyl-R²⁵—; wherein R⁸, R⁹ and R¹⁰independently of each other may be optionally substituted on carbon byone or more R¹⁸;

R¹⁸ is selected from hydroxy, amino, N—(C₁₋₆alkyl)amino,C₁₋₆alkanoylamino, C₁₋₆alkylsulphonylamino, carbocyclyl-R²⁷— orheterocyclyl-R²⁸—; wherein R¹⁸ may be optionally substituted on carbonby one or more R²⁰; and wherein if said heterocyclyl contains an —NH—moiety that nitrogen may be optionally substituted by a group selectedfrom R¹;

R²⁰ is selected from halo, amino, C₁₋₆alkyl, N,N—(C₁₋₆alkyl)₂amino,C₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino, carbocyclyl-R³⁵— orheterocyclyl-R³⁶—; wherein R²⁰ may be optionally substituted on carbonby one or more R³;

R²¹ is selected from C₁₋₆alkylsulphonyl;

R²³ is dimethylamino or phenyl; and

R²⁷, R²⁸, R³⁵ and R³⁶ are independently selected from a direct bond,—C(O)N(R³¹)—, —NH═CH— or —SO₂N(R³²)—; wherein R³¹ and R³² areindependently selected from hydrogen or C₁₋₆alkyl;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ is C₁₋₆alkyl, C₁₋₆alkoxy or carbocyclyl;

R² is hydrogen;

X³ or X⁴ is ═N—, X¹ and X² and the other of X³ and X⁴ are independentlyselected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—;

R³ is hydrogen;

R⁴ and R³⁴ are independently selected from hydrogen or C₁₋₆alkyl;wherein R⁴ and R³⁴ may be independently optionally substituted on carbonby one or more R¹²; wherein R¹² is selected from hydroxy;

A is a direct bond;

Ring C is carbocyclyl or heterocyclyl;

R⁵ is selected from fluoro, acetylamino, mesylamino or cyclopropyl-R³⁷—;wherein R³⁷ is —C(O)N(R³¹)—; wherein R³¹ is hydrogen;

n is 1 or 2; wherein the values of R⁵ may be the same or different;

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halo, nitro,cyano, amino, carboxy, carbamoyl, C₁₋₆alkyl, C₁₋₆alkanoyl,N—(C₁₋₆alkyl)amino or carbocyclyl-R²⁵—; wherein R⁸, R⁹ and R¹⁰independently of each other may be optionally substituted on carbon byone or more R¹⁸;

R¹⁸ is selected from hydroxy, amino, N—(C₁₋₆alkyl)amino,C₁₋₆alkanoylamino, C₁₋₆alkylsulphonylamino, carbocyclyl-R²⁷— orheterocyclyl-R²⁸—; wherein R¹⁸ may be optionally substituted on carbonby one or more R²⁰; and wherein if said heterocyclyl contains an —NH—moiety that nitrogen may be optionally substituted by a group selectedfrom R²¹;

R²⁰ is selected from halo, amino, C₁₋₆alkyl, N,N—(C₁₋₆alkyl)₂amino,C₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino, carbocyclyl-R³⁵— orheterocyclyl-R³⁶—; wherein R²⁰ may be optionally substituted on carbonby one or more R²³;

R²¹ is selected from C₁₋₆alkylsulphonyl;

R²³ is dimethylamino or phenyl; and

R²⁷, R²⁸, R³⁵ and R³⁶ are independently selected from a direct bond,—C(O)N(R³¹)—, —NH═CH— or —SO₂N(R³²)—; wherein R³¹ and R³² areindependently selected from hydrogen or C₁₋₆alkyl;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ is isopropoxy or cyclopropyl;

R² is hydrogen;

X³ or X⁴ is ═N—, X¹ and X² and the other of X³ and X⁴ are independentlyselected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—;

R³ is hydrogen;

R⁴ is selected from hydrogen, methyl or hydroxymethyl;

R³⁴ is hydrogen;

A is a direct bond;

Ring C is phenyl;

R⁵ is fluoro;

n is 1; and

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, fluoro, chloro,nitro, cyano, amino, carbamoyl, aminomethyl, acetylaminomethyl,mesylaminomethyl, 2-oxopyrrolidin-5-ylcarbonylaminomethyl and(2-aminoacetyl)aminomethyl;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ is methyl, t-butyl, isopropoxy or cyclopropyl;

R² is hydrogen;

X³ or X⁴ is ═N—, X¹ and X² and the other of X³ and X⁴ are independentlyselected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—;

R³ is hydrogen;

R⁴ is selected from hydrogen, methyl or hydroxymethyl;

R³⁴ is selected from hydrogen or hydroxymethyl;

A is a direct bond;

Ring C is phenyl;

R⁵ is fluoro;

n is 1; and

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, fluoro, chloro,nitro, cyano, amino, carbamoyl, aminomethyl, acetylaminomethyl,mesylaminomethyl, 2-oxopyrrolidin-5-ylcarbonylaminomethyl and(2-aminoacetyl)aminomethyl;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ is methyl, t-butyl, isopropoxy or cyclopropyl;

R² is hydrogen;

X³ or X⁴ is ═N—, X¹ and X² and the other of X³ and X⁴ are independentlyselected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—;

R³ is hydrogen;

R⁴ and R³⁴ are independently selected from hydrogen, methyl orhydroxymethyl;

A is a direct bond;

Ring C is phenyl;

R⁵ is fluoro;

n is 1;

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, fluoro, chloro,nitro, cyano, amino, carboxy, carbamoyl, formyl, methylamino,hydroxymethyl, acetylaminomethyl, (2-aminoacetyl)aminomethyl,(2-morpholinoacetyl)aminomethyl,(R)-2-oxopyrrolidin-5-yl-carbonylaminomethyl,(S)-2-oxopyrrolidin-5-yl-carbonylaminomethyl,(R,S)-2-oxopyrrolidin-5-yl-carbonylaminomethyl,isoxaxol-5-yl-carbonylaminomethyl, mesylaminomethyl, morpholinomethyl,benzoylaminomethyl, pyrid-3-yl-carbonylaminomethyl,6-dimethylaminopyrid-3-yl-carbonylaminomethyl,6-morpholinopyrid-3-yl-carbonylaminomethyl,pyrid-4-yl-carbonylaminomethyl,5-methylisoxaxol-4-yl-carbonylaminomethyl,thien-2-yl-carbonylaminomethyl,4-dimethylaminobenzylcarbonylaminomethyl,2-(N-(isopropyl)-N-(mesyl)amino)acetylaminomethyl,2-(N-(phenethyl)-N-(mesyl)amino)acetylaminomethyl,1-mesylpiperidin-1-ylcarbonylaminomethyl,2-(pyrid-3-yl)acetylaminomethyl,tetrahydro-2H-thiopyran-4-yl-carbonylaminomethyl,2-(thien-2-yl)acetylcarbonylaminomethyl,2-(thien-3-yl)acetylcarbonylaminomethyl, 3-phenylpropionylaminomethyl,2-(N-benzoyl-N-methylamino)acetylaminomethyl,4-dimethylaminobenzoylaminomethyl, phenylsulphonylaminomethyl,2-amino-3-methylbutanoylaminomethyl, cyclopropylcarbonylaminomethyl,pyrrol-2-yl-carbonylaminomethyl,tetrahydrofuran-2-yl-carbonylaminomethyl,furan-2-yl-carbonylaminomethyl, cyclopropylsulphonylaminomethyl,(cyclopropylimino)methyl, methylaminomethyl, trifluoromesylaminomethyl,isopropyl, isopropylamino or methylamino;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ is methyl, t-butyl, isopropoxy or cyclopropyl;

R² is hydrogen;

X³ or X⁴ is ═N—, X¹ and X² and the other of X³ and X⁴ are independentlyselected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—;

R³ is hydrogen;

R⁴ and R³⁴ are independently selected from hydrogen, methyl orhydroxymethyl;

A is a direct bond;

Ring C is phenyl, pyrid-2-yl, pyrid-3-yl or pyrimidin-2-yl;

R⁵ is selected from fluoro, acetylamino, mesylamino orcyclopropylcarbonylamino;

n is 1 or 2; wherein the values of R⁵ may be the same or different;

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, fluoro, chloro,iodo, nitro, cyano, amino, carboxy, carbamoyl, formyl, methylamino,hydroxymethyl, acetylaminomethyl, (2-aminoacetyl)aminomethyl,(2-morpholinoacetyl)aminomethyl,(R)-2-oxopyrrolidin-5-yl-carbonylaminomethyl,(S)-2-oxopyrrolidin-5-yl-carbonylaminomethyl,(R,S)-2-oxopyrrolidin-5-yl-carbonylaminomethyl,isoxaxol-5-yl-carbonylaminomethyl, mesylaminomethyl, morpholinomethyl,benzoylaminomethyl, pyrid-3-yl-carbonylaminomethyl,6-dimethylaminopyrid-3-yl-carbonylaminomethyl,6-morpholinopyrid-3-yl-carbonylaminomethyl,pyrid-4-yl-carbonylaminomethyl,5-methylisoxaxol-4-yl-carbonylaminomethyl,thien-2-yl-carbonylaminomethyl,4-dimethylaminobenzylcarbonylaminomethyl,2-(N-(isopropyl)-N-(mesyl)amino)acetylaminomethyl,2-(N-(phenethyl)-N-(mesyl)amino)acetylaminomethyl,1-mesylpiperidin-1-ylcarbonylaminomethyl,2-(pyrid-3-yl)acetylaminomethyl,tetrahydro-2H-thiopyran-4-yl-carbonylaminomethyl,2-(thien-2-yl)acetylcarbonylaminomethyl,2-(thien-3-yl)acetylcarbonylaminomethyl, 3-phenylpropionylaminomethyl,2-(N-benzoyl-N-methylamino)acetylaminomethyl,4-dimethylaminobenzoylaminomethyl, phenylsulphonylaminomethyl,2-amino-3-methylbutanoylaminomethyl, cyclopropylcarbonylaminomethyl,pyrrol-2-yl-carbonylaminomethyl,tetrahydrofuran-2-yl-carbonylaminomethyl,furan-2-yl-carbonylaminomethyl, cyclopropylsulphonylaminomethyl,(cyclopropylimino)methyl, methylaminomethyl, trifluoromesylaminomethyl,isopropyl, isopropylamino or methylamino;

or a pharmaceutically acceptable salt thereof.

In a further aspect of the invention there is provided a compound offormula (Ia):

wherein R^(a) is nitro or amino; and other variable groups are asdefined herein above.

In a further aspect of the invention there is provided a compound offormula (Ib):

wherein R^(b) is nitro or amino; and other variable groups are asdefined herein above.

In another aspect of the invention, preferred compounds of the inventionare any one of the Examples or a pharmaceutically acceptable saltthereof.

In another aspect of the invention, preferred compounds of the inventionare any one of Examples 1, 6, 11, 16, 64, 110, 112, 113, 119 and 120 ora pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use as amedicament.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe manufacture of a medicament for use in the inhibition of Trkactivity.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe manufacture of a medicament for use in the treatment or prophylaxisof cancer.

In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for usein the manufacture of a medicament for use in the treatment of cancer ina warm-blooded animal such as man.

In an additional embodiment the present invention provides a compound ofthe formula (a), or a pharmaceutically acceptable salt thereof, for usein the manufacture of a medicament for use in the treatment orprophylaxis of cancers (solid tumors and leukemia), fibroproliferativeand differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi'ssarcoma, haemangioma, acute and chronic nephropathies, atheroma,atherosclerosis, arterial restenosis, autoimmune diseases, acute andchronic inflammation, bone diseases and ocular diseases with retinalvessel proliferation in a warm-blooded animal such as man.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe manufacture of a medicament for use in the production of ananti-proliferative effect.

In an additional embodiment the present invention provides a method ofinhibiting Trk activity comprising administering to a host in need ofsuch treatment a therapeutically effective amount of a compound offormula (a), or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a method forthe treatment of cancer comprising administering to a host in need ofsuch treatment a therapeutically effective amount of a compound offormula (a), or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a method forthe treatment or prophylaxis of cancer comprising administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a method forthe treatment or prophylaxis of cancers (solid tumors and leukemia),fibroproliferative and differentiative disorders, psoriasis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation in a warm-bloodedanimal such as man comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

In an additional embodiment the present invention provides a method ofproducing an anti-proliferative effect in a warm-blooded animal, such asman, in need of such treatment which comprises administering to saidanimal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in theinhibition of Trk activity.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in thetreatment of cancer.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in thetreatment or prophylaxis of cancer.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in thetreatment or prophylaxis of cancers (solid tumors and leukemia),fibroproliferative and differentiative disorders, psoriasis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in theproduction of an anti-proliferative effect in a warm-blooded animal suchas man.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe inhibition of Trk activity.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe treatment or prophylaxis of cancer.

In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for usein the treatment of cancer in a warm-blooded animal such as man.

In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for usein the treatment or prophylaxis of cancers (solid tumours andleukaemia), fibroproliferative and differentiative disorders, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation in a warm-bloodedanimal such as man.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe production of an anti-proliferative effect.

In one embodiment where the inhibition of Trk activity is referred toparticularly this refers to the inhibition of Trk A activity.

In another embodiment where the inhibition of Trk activity is referredto particularly this refers to the inhibition of Trk B activity.

Where the treatment (or prophylaxis) of cancer is referred to,particularly it refers to the treatment (or prophylaxis) of mesoblasticnephroma, mesothelioma, acute myeloblastic leukemia, acute lymphocyticleukemia, multiple myeloma, oesophageal cancer, myeloma, hepatocellular,pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposisarcoma, ovarian cancer, breast cancer including secretory breastcancer, colorectal cancer, prostate cancer including hormone refractoryprostate cancer, bladder cancer, melanoma, lung cancer—non small celllung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer,head and neck cancer, renal cancer, lymphoma thyroid cancer includingpapillary thyroid cancer, mesothelioma, leukaemia, tumours of thecentral and peripheral nervous system, melanoma, fibrosarcoma includingcongenital fibrosarcoma and osteosarcoma. More particularly it refers toprostate cancer. In addition, more particularly it refers to SCLC,NSCLC, colorectal cancer, ovarian cancer and/or breast cancer. In afurther aspect it refers to hormone refractory prostate cancer.

In a further aspect of the present invention provides a process forpreparing a compound of formula (I) or a pharmaceutically acceptablesalt thereof which process (wherein variable groups are, unlessotherwise specified, as defined in formula (I)) comprises of:

Process a) reaction of a compound of formula (II):

wherein Pg is a nitrogen protecting group; with a compound of formula(III):

wherein L is a displaceable group;Process b) for compounds of formula (I) wherein R⁴ is hydroxymethyl andR³⁴ is hydrogen; reaction of a compound of formula (II) with an epoxideof formula (IV):

Process c) reacting a compound of formula (V):

with hydrazine;Process d) reacting a compound of formula (VI):

wherein L is a displaceable group; with an amine of formula (VII):

Process e) reacting a compound of formula (VIII):

wherein L is a displaceable group; with an amine of formula (IX):

Process f) reacting an amine of formula (X):

with a compound of formula (XI):

wherein L is a displaceable group; and thereafter if necessary:

-   i) converting a compound of the formula (I) into another compound of    the formula (I);-   ii) removing any protecting groups;-   iii) forming a pharmaceutically acceptable salt.

L is a displaceable group, suitable values for L are for example, a haloor sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxyor toluene-4-sulphonyloxy group.

Pg is a nitrogen protecting group. Suitable values for Pg are describedherein below.

Specific reaction conditions for the above reactions are as follows.

Process a) Compounds of formula (II) and (III) may be reacted togetherunder standard nucleophilic addition reactions for example in thepresence of a suitable base such as potassium carbonate and a suitablesolvent such as DMF and at a temperature in the range from 25 to 100° C.

Compounds of the formula (II) may be prepared according to Scheme 1:

wherein Pg is a nitrogen protecting group. Suitable values for Pg aredefined below; and wherein L is a displaceable group as defined above.

Compounds of formula (III), (IIa) and (IIb) are commercially availablecompounds, or they are known in the literature, or they are prepared bystandard processes known in the art.

Process b) Compounds of formula (II) and (IV) may be reacted togetherunder epoxide ring opening reaction conditions for example in thepresence of a suitable catalyst such as LiClO₄, NaClO₄, Mg(ClO₄)₂ and asuitable solvent such as CH₃CN and at a temperature in the range from 25to 80° C.

Compounds of formula (IV) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

Process c) The s reaction may be carried out in a suitable solvent, forexample, an alcohol such as ethanol or butanol at a temperature in therange from 50-120° C., in particular in the range from 70-100° C.

Compounds of the formula (V) may be prepared according to Scheme 2:

Compounds of the formula (Va) are commercially available compounds, orthey are known in the literature, or they are prepared by standardprocesses known in the art.

Process d) Compounds of formula (VI) and (VII) may be reacted togetherunder the conditions listed in Process a).

Compounds of formula (VI) may be prepared according to Scheme 3:

wherein L is a displaceable group as defined herein above.

Compounds of the formula (VIa) and (VII) are commercially availablecompounds, or they are known in the literature, or they are prepared bystandard processes known in the art.

Process e) Compounds of formula (VIII) and (IX) may be reacted togetherunder the conditions listed in Process a).

Compounds of formula (VIII) may be prepared according to Scheme 4:

Compounds of the formula (IX) are commercially available compounds, orthey are known in the literature, or they are prepared by standardprocesses known in the art.

Process f) Compounds of formula (X) and (XI) may be reacted togetherunder the conditions listed in Process a).

Compounds of formula (X) may be prepared according to Scheme 5:

wherein L is a displaceable group as defined herein above.

Compounds of the formula (Xa) and (XI) are commercially availablecompounds, or they are known in the literature, or they are prepared bystandard processes known in the art.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

Definitions

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₆alkyl” and “C₁₋₄alkyl” include methyl, ethyl, propyl,isopropyl and t-butyl. However, references to individual alkyl groupssuch as ‘propyl’ are specific for the straight-chained version only andreferences to individual branched chain alkyl groups such as ‘isopropyl’are specific for the branched-chain version only. A similar conventionapplies to other radicals. The term “halo” refers to fluoro, chloro,bromo and iodo.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

A “heterocyclyl” is a saturated, partially saturated or unsaturated,mono or bicyclic ring containing 4-12 atoms of which at least one atomis chosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked, wherein a —CH₂— group canoptionally be replaced by a —C(O)—, and a ring sulphur atom may beoptionally oxidised to form the S-oxides. Examples and suitable valuesof the term “heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl,pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl,thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino,pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl,imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl,N-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone,4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide. Further examplesand suitable values of the term “heterocyclyl” are morpholino,piperazinyl and pyrrolidinyl. In one aspect of the invention a“heterocyclyl” is a saturated, partially saturated or unsaturated, monoor bicyclic ring containing 5 or 6 atoms of which at least one atom ischosen from nitrogen, sulphur or oxygen, it may, unless otherwisespecified, be carbon or nitrogen linked, a —CH₂— group can optionally bereplaced by a —C(O)— and a ring sulphur atom may be optionally oxidisedto form the S-oxides. Further examples and suitable values of the term“heterocyclyl” are tetrahydrofuranyl, furanyl, pyrrolyl, isoxaxolyl,piperidinyl, thienyl, pyridyl, tetrahydro-2H-thiopyranyl, morpholino and2-oxopyrrolidinyl.

A “carbocyclyl” is a saturated, partially saturated or unsaturated, monoor bicyclic carbon ring that contains 3-12 atoms; wherein a —CH₂— groupcan optionally be replaced by a —C(O)—. Particularly “carbocyclyl” is amonocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9or 10 atoms. Suitable values for “carbocyclyl” include cyclopropyl,cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.

Where “one of X¹, X², X³ and X⁴ is ═N—, the other three areindependently selected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—” it is to beunderstood that this means one of X¹, X², X³ and X⁴ is ═N—, one of theother three is ═CR⁸—, one of the remaining two is ═CR⁹— and the last is═CR¹⁰—. For example the scenario wherein X¹ is ═N—, X² is ═CR⁸—, X³ is═CR⁹— and X⁴ is ═CR¹⁰— is embraced by this definition as is X³ is ═N—,X¹ is ═CR⁸—, X² is ═CR⁹— and X⁴ is ═CR¹⁰—. The ring containing X¹, X²,X³ and X⁴ is thus a pyridine ring.

The term “C_(m-n)” or “C_(m-n) group” used alone or as a prefix, refersto any group having m to n carbon atoms.

The term “optionally substituted” refers to either groups, structures,or molecules that are substituted and those that are not substituted.

An example of “C₁₋₆alkanoyloxy” is acetoxy. Examples of“C₁₋₆alkoxycarbonyl” include C₁₋₄alkoxycarbonyl, methoxycarbonyl,ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of “C₁₋₆alkoxy”include C₁₋₄alkoxy, C₁₋₃alkoxy, methoxy, ethoxy and propoxy. Examples of“C₁₋₆alkoxyimino” include C₁₋₄alkoxyimino, C₁₋₃alkoxyimino,methoxyimino, ethoxyimino and propoxyimino. Examples of“C₁₋₆alkanoylamino” include formamido, acetamido and propionylamino.Examples of “C₁₋₆alkylS(O)_(a) wherein a is 0 to 2” includeC₁₋₄alkylsulphonyl, methylthio, ethylthio, methylsulphinyl,ethylsulphinyl, mesyl and ethylsulphonyl. Examples of “C₁₋₆alkylthio”include methylthio and ethylthio. Examples of “C₁₋₆alkylsulphonylamino”include methylsulphonylamino and ethylsulphsulphonylamino. Examples of“C₁₋₆alkanoyl” include C₁₋₄alkanoyl, formyl, propionyl and acetyl.Examples of “N—(C₁₋₆alkyl)amino” include methylamino and ethylamino.Examples of “N,N—(C₁₋₆alkyl)₂amino” include di-N-methylamino,di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of “C₂₋₆alkenyl”are vinyl, alkyl and 1-propenyl. Examples of “C₂₋₆alkynyl” are ethynyl,1-propynyl and 2-propynyl. Examples of “N—(C₁₋₆alkyl)sulphamoyl” areN-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of“N—(C₁₋₆alkyl)₂sulphamoyl” are N,N-(dimethyl)sulphamoyl andN-(methyl)-N-(ethyl)sulphamoyl. Examples of “N—(C₁₋₆alkyl)carbamoyl” areN—(C₁₋₄alkyl)carbamoyl, methylaminocarbonyl and ethylaminocarbonyl.Examples of “N,N—(C₁₋₆alkyl)₂carbamoyl” are N,N—(C₁₋₄alkyl)₂carbamoyl,dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of“C₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino” include N-mesyl-N-methylaminoand N-mesyl-N-isopropylamino.

“RT” or “rt” means room temperature.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

It should be noted that the pyrazoles claimed in this invention arecapable to exist in different resonance structures and thus thepyrazoles claimed herein include all possible resonance structures, forexample optical isomers, diastereoisomers and geometric isomers and alltautomeric forms of the compounds of the formula (I).

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms.

Formulations

Compounds of the present invention may be administered orally,parenteral, buccal, vaginal, rectal, inhalation, insufflation,sublingually, intramuscularly, subcutaneously, topically, intranasally,intraperitoneally, intrathoracially, intravenously, epidurally,intrathecally, intracerebroventricularly and by injection into thejoints.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, when determining the individualregimen and dosage level as the most appropriate for a particularpatient.

An effective amount of a compound of the present invention for use intherapy of cancer is an amount sufficient to symptomatically relieve ina warm-blooded animal, particularly a human the symptoms of cancer, toslow the progression of cancer, or to reduce in patients with symptomsof cancer the risk of getting worse.

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substance, which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing suppository compositions, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmolds and allowed to cool and solidify.

Suitable carriers include magnesium carbonate, magnesium stearate, talc,lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and thelike.

Some of the compounds of the present invention are capable of formingsalts with various inorganic and organic acids and bases and such saltsare also within the scope of this invention. Examples of such acidaddition salts include acetate, adipate, ascorbate, benzoate,benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate,camphorsulfonate, choline, citrate, cyclohexyl sulfamate,diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate,hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate,malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate,nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate,diphosphate, picrate, pivalate, propionate, quinate, salicylate,stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate(p-toluenesulfonate), trifluoroacetate, and undecanoate. Base saltsinclude ammonium salts, alkali metal salts such as sodium, lithium andpotassium salts, alkaline earth metal salts such as aluminum, calciumand magnesium salts, salts with organic bases such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, ornithine, and so forth. Also, basicnitrogen-containing groups may be quaternized with such agents as: loweralkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkylsulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chainhalides such as decyl, lauryl, myristyl and stearyl halides; aralkylhalides like benzyl bromide and others. Non-toxicphysiologically-acceptable salts are preferred, although other salts arealso useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water, which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion-exchange resin.

In order to use a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof for the therapeutic treatment (includingprophylactic treatment) of mammals including humans, it is normallyformulated in accordance with standard pharmaceutical practice as apharmaceutical composition.

In addition to the compounds of the present invention, thepharmaceutical composition of this invention may also contain, or beco-administered (simultaneously or sequentially) with, one or morepharmacological agents of value in treating one or more diseaseconditions referred to herein.

The term composition is intended to include the formulation of theactive component or a pharmaceutically acceptable salt with apharmaceutically acceptable carrier. For example this invention may beformulated by means known in the art into the form of, for example,tablets, capsules, aqueous or oily solutions, suspensions, emulsions,creams, ointments, gels, nasal sprays, suppositories, finely dividedpowders or aerosols or nebulisers for inhalation, and for parenteral use(including intravenous, intramuscular or infusion) sterile aqueous oroily solutions or suspensions or sterile emulsions.

Liquid form compositions include solutions, suspensions, and emulsions.Sterile water or water-propylene glycol solutions of the activecompounds may be mentioned as an example of liquid preparations suitablefor parenteral administration. Liquid compositions can also beformulated in solution in aqueous polyethylene glycol solution. Aqueoussolutions for oral administration can be prepared by dissolving theactive component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

The pharmaceutical compositions can be in unit dosage form. In suchform, the composition is divided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities of thepreparations, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of any of thesepackaged forms.

Combinations

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:

-   (i) antiproliferative/antineoplastic drugs and combinations thereof,    as used in medical oncology, such as alkylating agents (for example    cis-platin, carboplatin, cyclophosphamide, nitrogen mustard,    melphalan, chlorambucil, busulphan and nitrosoureas);    antimetabolites (for example antifolates such as fluoropyrimidines    like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine    arabinoside and hydroxyurea); antitumour antibiotics (for example    anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,    epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);    antimitotic agents (for example vinca alkaloids like vincristine,    vinblastine, vindesine and vinorelbine and taxoids like taxol and    taxotere); and topoisomerase inhibitors (for example    epipodophyllotoxins like etoposide and teniposide, amsacrine,    topotecan and camptothecin);-   (ii) cytostatic agents such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),    oestrogen receptor down regulators (for example fulvestrant),    antiandrogens (for example bicalutamide, flutamide, nilutamide and    cyproterone acetate), LHRH antagonists or LHRH agonists (for example    goserelin, leuprorelin and buserelin), progestogens (for example    megestrol acetate), aromatase inhibitors (for example as    anastrozole, letrozole, vorazole and exemestane) and inhibitors of    5α-reductase such as finasteride;-   (iii) agents which inhibit cancer cell invasion (for example    metalloproteinase inhibitors like marimastat and inhibitors of    urokinase plasminogen activator receptor function);-   (iv) inhibitors of growth factor function, for example such    inhibitors include growth factor antibodies, growth factor receptor    antibodies (for example the anti-erbb2 antibody trastuzumab    [Herceptin™] and the anti-erbb1 antibody cetuximab [C225]), farnesyl    transferase inhibitors, tyrosine kinase inhibitors and    serine/threonine kinase inhibitors, for example inhibitors of the    epidermal growth factor family (for example EGFR family tyrosine    kinase inhibitors such as-   N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine    (gefitinib, AZD1839),    N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine    (erlotinib, OSI-774) and-   6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine    (CI 1033)), for example inhibitors of the platelet-derived growth    factor family and for example inhibitors of the hepatocyte growth    factor family;-   (v) antiangiogenic agents such as those which inhibit the effects of    vascular endothelial growth factor, (for example the anti-vascular    endothelial cell growth factor antibody bevacizumab [Avastin™],    compounds such as those disclosed in International Patent    Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354)    and compounds that work by other mechanisms (for example linomide,    inhibitors of integrin αcvβ3 function and angiostatin);-   (vi) vascular damaging agents such as Combretastatin A4 and    compounds disclosed in International Patent Applications WO    99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO    02/08213;-   (vii) antisense therapies, for example those which are directed to    the targets listed above, such as ISIS 2503, an anti-ras antisense;-   (viii) gene therapy approaches, including for example approaches to    replace aberrant genes such as aberrant p53 or aberrant BRCA1 or    BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such    as those using cytosine deaminase, thymidine kinase or a bacterial    nitroreductase enzyme and approaches to increase patient tolerance    to chemotherapy or radiotherapy such as multi-drug resistance gene    therapy; and-   (ix) immunotherapy approaches, including for example ex-vivo and    in-vivo approaches to increase the immunogenicity of patient tumour    cells, such as transfection with cytokines such as interleukin 2,    interleukin 4 or granulocyte-macrophage colony stimulating factor,    approaches to decrease T-cell anergy, approaches using transfected    immune cells such as cytokine-transfected dendritic cells,    approaches using cytokine-transfected tumour cell lines and    approaches using anti-idiotypic antibodies.-   (x) other treatment regimes including: dexamethasone, proteasome    inhibitors (including bortezomib), isotretinoin (13-cis retinoic    acid), thalidomide, revemid, Rituxamab, ALIMTA, Cephalon's kinase    inhibitors CEP-701 and CEP-2563, anti-Trk or anti-NGF monoclonal    antibodies, targeted radiation therapy with    131I-metaiodobenzylguanidine (131I-MIBG), anti-G(D2) monoclonal    antibody therapy with or without granulocyte-macrophage    colony-stimulating factor (GM-CSF) following chemotherapy.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention, or pharmaceutically acceptable salts thereof, within thedosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

Synthesis

The compounds, or pharmaceutically acceptable salts thereof, of thepresent invention can be prepared in a number of ways well known to oneskilled in the art of organic synthesis. The compounds, orpharmaceutically acceptable salts thereof, of the present invention canbe synthesized using the methods described below, together withsynthetic methods known in the art of synthetic organic chemistry, orvariations thereon as appreciated by those skilled in the art. Suchmethods include, but are not limited to, those described below. Allreferences cited herein are hereby incorporated in their entirety byreference.

The novel compounds, or pharmaceutically acceptable salts thereof, ofthis invention may be prepared using the reactions and techniquesdescribed herein. The reactions are performed in solvents appropriate tothe reagents and materials employed and are suitable for thetransformations being effected. Also, in the description of thesynthetic methods described below, it is to be understood that allproposed reaction conditions, including choice of solvent, reactionatmosphere, reaction temperature, duration of the experiment and workupprocedures, are chosen to be the conditions standard for that reaction,which should be readily recognized by one skilled in the art. It isunderstood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reactions proposed. Such restrictionsto the substituents, which are compatible with the reaction conditions,will be readily apparent to one skilled in the art and alternate methodsmust then be used.

EXAMPLES

The invention will now be further described with reference to thefollowing illustrative examples in which, unless stated otherwise:

-   -   (i) temperatures are given in degrees Celsius (° C.); operations        are carried out at room temperature or ambient temperature, that        is, in a range of 18-25° C.;    -   (ii) organic solutions were dried over anhydrous magnesium        sulfate; evaporation of organic solvent was carried out using a        rotary evaporator under reduced pressure (4.5-30 mmHg) with a        bath temperature of up to 60° C.;    -   (iii) chromatography means flash chromatography on silica gel;        thin layer chromatography (TLC) was carried out on silica gel        plates;    -   (iv) in general, the course of reactions was followed by TLC or        liquid chromatography/mass spectroscopy (LC/MS) and reaction        times are given for illustration only;    -   (v) final products have satisfactory proton nuclear magnetic        resonance (NMR) spectra and/or mass spectra data;    -   (vi) yields are given for illustration only and are not        necessarily those which can be obtained by diligent process        development; preparations were repeated if more material was        required;    -   (vii) when given, NMR data is in the form of delta values for        major diagnostic protons, given in part per million (ppm)        relative to tetramethylsilane (TMS) as an internal standard,        determined at 300 MHz in DMSO-d₆ unless otherwise stated;    -   (viii) chemical symbols have their usual meanings;    -   (ix) solvent ratio was given in volume:volume (v/v) terms.    -   (x) the following abbreviations have been used:

EtOAc ethyl acetate; ether diethyl ether; EtOH ethanol; THFtetrahydrofuran; TFP tetrafluorophenyl; DIEA diisopropylethylamine; DMAP4-dimethylaminopyridine; NMP N-methylpyridinone; MTBE methyl tert-butylether; DMF N,N-dimethylformamide; HBTU2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate; DCE dichloroethane; TFP resin tetrafluorophenolresin; MeOH methanol; and DCM dichloromethane.

Example 1(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile

A portion of2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoronicotinonitrile(Method 1; 0.8 g, 2.8 mmol) and (S)-1-(4-fluorophenyl)ethanamine (0.8 g,5.6 mmol) were added to a solution of n-BuOH (4 ml) and DIEA (0.5 g, 3.7mmol) in a sealed tube. The reaction was heated to 140° C. for 48 hrs,then cooled to 25° C. and concentrated. The resulting residue waspurified by column chromatography (DCM-MeOH=50:1) to give the titlecompound (0.55 g, 50%). ¹H NMR (400 MHz, CDCl₃) δ 8.44 (br s, 1H),7.37-7.33 (m, 2H), 7.27 (d, J=9.6 Hz, 1H), 7.07-7.03 (m, 2H), 6.11 (s,1H), 5.24-5.20 (m, 2H), 1.87-1.83 (m, 1H), 1.60 (d, J=6.2 Hz, 3H),1.01-0.98 (m, 2H), 0.79-0.65 (m, 2H). MS: Calcd.: 380. Found: [M+H]⁺381.

Example 2(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinamide

To a solution of(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile(Example 1; 0.5 g, 1.3 mmol) in MeOH (50 ml), was added a 25% aqueoussolution (2 ml) of KOH (400 mg) at 25° C., followed by the addition of0.1 ml of 30% H₂O₂. The resulting dark red solution was heated to 65° C.for 1 h, cooled to 25° C., and concentrated. The resulting residue wasdissolved in EtOAc (50 ml), washed with water (30 ml), dried, filteredand concentrated. The resulting solid was purified by columnchromatography (DCM-MeOH=30:1) to give the title compound (0.30 g, 60%).¹H NMR (400 MHz, CDCl₃) δ 9.06 (d, J=7.0 Hz, 1H), 7.90 (br s, 1H),7.35-7.32 (m, 2H), 7.25 (d, J=7.2 Hz, 1H), 7.00-6.95 (m, 2H), 6.00 (brs, 1H), 5.66 (br s, 2H), 5.21-5.17 (m, 1H), 1.86-1.82 (m, 1H), 1.54 (d,J=6.8 Hz, 3H), 0.96-0.92 (m, 2H), 0.69-0.67 (m, 2H). MS: Calcd.: 398.Found: [M+H]⁺ 399.

Example 3(S)-3-(Aminomethyl)-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine

To a MeOH solution (5 ml) was added(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile (Example 1;0.15 g, 0.4 mmol), conc. HCl (0.1 ml), and Pd (10 wt. %, dry basis, onactivated carbon, 0.12 g). The mixture was then flushed with N₂,evacuated, and then placed under 40 psi of H₂ for 6 hrs. The reactionwas then evacuated, flushed with N₂, filtered, washed with MeOH (3×30ml), and concentrated. The resulting solid was dissolved in the mixtureof DCM-MeOH (50:1, 100 ml), and a saturated aqueous solution of Na₂CO₃(100 ml) was added, and the mixture was shaken vigorously for 30 min.The layers were then allowed to separate, and the aqueous layer wasextracted with DCM (3×100 ml). The combined organic layers were dried,filtered and concentrated. The resulting solid was purified by columnchromatography (DCM-MeOH=9:1) to give the title compound (0.09 g, 58%).¹H NMR (400 MHz, CD₃OD) δ 7.42-7.38 (m, 2H), 7.15 (d, J=11. Hz, 1H),7.02-6.97 (m, 2H), 5.15-5.08 (m, 1H), 3.74 (s, 2H), 1.88-1.81 (m, 1H),1.54 (d, J=7.0 Hz, 3H), 0.93-0.92 (m, 2H), 0.67-0.63 (m, 2H). MS:Calcd.: 384. Found: [M+H]⁺ 385.

Example 4(S)—N-((6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)pyridin-3-yl)methyl)acetamide

A round bottom flask was charged with(S)-3-(aminomethyl)-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine(Example 3; 0.08 g, 0.2 mmol) and acetic acid loaded TFP resin (1.4mmol/g loading, 0.2 mmol) in mixture of THF-DCM (1:1, 3 ml) at 0° C. Theresulting solution was shaken vigorously at 0° C. for 45 min andfiltered. The resulting resin was washed with a THF-DCM solution (1:1,3×5 ml for 30 min. each). The resulting organic layers were combined andconcentrated. The resulting solid was purified by reverse-phase columnchromatography (5-50% CH₃CN in H₂O over 400 ml) to give the titlecompound (0.045 g, 50%). ¹H NMR (400 MHz, CD₃OD) δ 7.34-7.33 (m, 2H),7.11 (d, J=10.7 Hz, 1H), 7.01-6.97 (m, 2H), 5.14-5.04 (m, 1H), 4.30-4.17(m, 2H), 1.99 (s, 3H), 1.88-1.81 (m, 1H), 1.50 (d, J=6.8 Hz, 3H),0.94-0.92 (m, 2H), 0.67-0.63 (m, 2H). MS: Calcd.: 426. Found: [M+H]⁺427.

Example 5(S)—N-((6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluoro-Phenyl)ethylamino)pyridin-3-yl)methyl)methanesulfonamide

A round bottom flask was charged with(S)-3-(aminomethyl)-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine(Example 3; 0.025 g, 0.065 mmol), methanesulfonic acid loaded TFP resin(0.9 mmol/g loading, 0.065 mmol), DIEA (0.017 g, 0.13 mmol), DMAP (0.09g, 0.072 mmol), and THF (5 ml). The resulting solution was shakenvigorously at 60° C. for 8 hrs. The reaction was filtered and theresulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30min. each). The resulting organic layers were combined and concentrated.The resulting solid was purified by reverse-phase column chromatography(5-50% CH₃CN in H₂O over 400 ml) to give the title compound (0.016 g,53%). ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.39 (m, 2H), 7.14 (d, J=10.7 Hz,1H), 7.01-6.97 (m, 2H), 5.16-5.09 (m, 1H), 4.15-4.06 (m, 2H), 2.99 (s,3H), 1.88-1.83 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 0.95-0.93 (m, 2H),0.66-0.64 (m, 2H). MS: Calcd.: 462. Found: [M+H]⁺ 463.

Example 6(R)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)nicotinonitrile

2-Chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoronicotinonitrile(Method 1; 0.5 g, 1.8 mmol) and (R)-2-amino-2-(4-fluorophenyl)ethanol(0.6 g, 3.6 mmol) were added to a solution of n-BuOH (4 ml) and DIEA(0.3 g, 2.3 mmol) in a sealed tube. The reaction was heated to 140° C.for 48 hrs, then cooled to 25° C. and concentrated. The resultingresidue was purified by column chromatography (DCM-MeOH=80:1) to givethe title compound (0.3 g, 40%). ¹H NMR (400 MHz, CD₃OD) δ 7.37-7.35 (m,3H), 7.05-7.00 (m, 2H), 5.99 (s, 1H), 5.20-5.11 (m, 1H), 3.90-3.77 (m,2H), 1.90-1.86 (m, 1H), 1.05-0.96 (m, 2H), 0.73-0.66 (m, 2H). MS:Calcd.: 396. Found: [M+H]⁺ 397.

Example 7(R)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)nicotinamide

(R)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)nicotinonitrile(Example 6; 0.07 g, 0.2 mmol), was placed in MeOH (5 ml) at 25° C. A 25%aqueous solution (0.2 ml) of KOH (50 mg) was then added, followed by theaddition of 0.05 ml of 30% H₂O₂. The resulting dark red solution washeated to 65° C. for 1 h, cooled to 25° C., and concentrated. Theresulting residue was dissolved in EtOAc (50 ml), washed with water (30ml), dried, filtered, and concentrated. The resulting solid was purifiedby column chromatography (DCM-MeOH=30:1) to give the title compound(0.065 g, 90%). ¹H NMR (400 MHz, CD₃OD) δ 7.69 (d, J=12.1 Hz, 1H),7.39-7.36 (m, 2H), 7.04-7.00 (m, 2H), 5.94 (s, 1H), 5.22-5.16 (m, 1H),3.87-3.75 (m, 2H), 1.91-1.84 (m, 1H), 0.98-0.96 (m, 2H), 0.74-0.69 (m,2H). MS: Calcd.: 414. Found: [M+H]⁺ 415.

Example 8(R)-2-(3-(Aminomethyl)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol

The mixture of(R)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)nicotinonitrile(Example 6; 0.13 g, 0.33 mmol), conc. HCl (0.1 ml), and Pd (10 wt. %,dry basis, on activated carbon, 0.12 g) in MeOH (5 ml) was flushed withN₂, evacuated, and then placed under H₂ (40 psi) for 6 hrs. The reactionwas then evacuated, flushed with N₂, filtered, washed with MeOH (3×30ml), and concentrated. The resulting solid was dissolved in the mixtureof DCM-MeOH (50:1, 100 ml), and a saturated aqueous solution of Na₂CO₃(100 ml) was added. The mixture was shaken vigorously for 30 min andallowed to separate. The aqueous layer was extracted with DCM (3×100ml). The combined organic layer was dried, filtered and concentrated.The resulting solid was purified by reverse-phase column chromatography(5-50% CH₃CN in H₂O over 400 ml) to give the title compound (0.074,57%). ¹H NMR (400 MHz, CD₃OD) δ 7.45-7.42 (m, 2H), 7.17 (d, J=11.1 Hz,1H), 7.04-7.00 (m, 2H), 5.72 (br s, 1H), 5.18-5.08 (m, 1H), 3.89-3.72(m, 4H), 1.87-1.83 (m, 1H), 0.94-0.92 (m, 2H), 0.69-0.65 (m, 2H). MS:Calcd.: 400. Found: [M+H]⁺ 401.

Example 9(R)—N-((6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)pyridin-3-yl)methyl)acetamide

(R)-2-(3-(Aminomethyl)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol(Example 8; 0.034 g, 0.085 mmol) and acetic acid loaded TFP resin (1.4mmol/g loading, 0.085 mmol) were placed in a THF-DCM solution (1:1, 3ml) at 0° C. The resulting suspension was shaken vigorously at 0° C. for45 min. The reaction was filtered and the resulting resin was washedwith a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resultingorganic layers were combined and concentrated. The resulting solid waspurified by reverse-phase column chromatography (5-50% CH₃CN in H₂O over400 ml) to give the title compound (0.018 g, 48%). ¹H NMR (400 MHz,CD₃OD) δ 7.42-7.36 (m, 2H), 7.12 (d, J=9.6 Hz, 1H), 7.04-6.99 (m, 2H),6.09 (br s, 1H), 5.19-5.02 (m, 1H), 4.36-4.17 (m, 2H), 3.83-3.71 (m,2H), 1.99 (s, 3H), 1.88-1.83 (m, 1H), 0.98-0.87 (m, 2H), 0.72-0.66 (m,2H). MS: Calcd.: 442. Found: [M+H]⁺ 443.

Example 10(R)—N-((6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)pyridin-3-yl)methyl)methanesulfonamide

A round bottom flask was charged with(R)-2-(3-(aminomethyl)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol(Example 8; 0.20 g, 0.50 mmol), methanesulfonic acid loaded TFP resin(0.9 mmol/g loading, 0.50 mmol), DIEA (0.13 g, 1.00 mmol), DMAP (0.067g, 0.067 mmol), and THF (10 ml). The resulting solution was shakenvigorously at 60° C. for 8 hrs. The reaction was filtered and theresulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30min. each). The resulting organic layers were combined and concentrated.The resulting solid was purified by reverse-phase column chromatography(5-50% CH₃CN in H₂O over 400 ml) to give the title compound (0.075 g,31%). ¹H NMR (400 MHz, CD₃OD) δ 7.50-7.41 (m, 2H), 7.15 (d, J=9.1 Hz,1H), 7.04-7.00 (m, 2H), 6.09 (br s, 1H), 5.22-5.03 (m, 1H), 4.20-4.07(m, 2H), 3.86-3.74 (m, 2H), 2.98 (s, 3H), 1.89-1.85 (m, 1H), 1.04-0.92(m, 2H), 0.78-0.66 (m, 2H). MS: Calcd.: 478; Found: [M+H]⁺ 479.

Example 11(R)-5-Fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile

2-Chloro-5-fluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile(Method 2; 1.6 g, 5.0 mmol) and (R)-2-amino-2-(4-fluorophenyl)ethanol(2.0 g, 11.0 mmol) were added to a solution of n-BuOH (8 ml) and DIEA(0.8 g, 6.0 mmol) in a sealed tube. The reaction was heated to 135° C.for 72 hrs, cooled to 25° C., and concentrated. The resulting residuewas purified by column chromatography (DCM-MeOH=50:1) to give the titlecompound (0.7 g, 31%). ¹H NMR (400 MHz, CD₃OD) δ 7.49 (d, J=9.5 Hz, 1H),7.41-7.38 (m, 2H), 7.07-7.02 (m, 2H), 5.40 (s, 1H), 5.10-5.01 (m, 1H),4.62-4.55 (m, 1H), 3.91-3.79 (m, 2H), 1.33-1.31 (m, 6H). MS: Calcd.:414. Found: [M+H]⁺ 415.

Example 12(R)-5-Fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinamide

(R)-5-Fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile (Example 11; 0.06 g, 0.1 mmol) was placed inMeOH (5 ml) at 25° C. A 25% aqueous solution (0.2 ml) of KOH (0.05 g,0.7 mmol) was then added, followed by the addition of 0.05 ml of 30%H₂O₂. The resulting dark red solution was heated to 65° C. for 1 h,cooled to 25° C., and concentrated. The resulting residue was dissolvedin EtOAc (50 ml), washed with water (30 ml), dried, filtered, andconcentrated. The resulting solid was purified by column chromatography(DCM-MeOH=30:1) to give the title compound (0.037 g, 60%). ¹H NMR (400MHz, CD₃OD) δ 7.75 (d, J=11.9 Hz, 1H), 7.43-7.39 (m, 2H), 7.06-7.02 (m,2H), 5.37 (br s, 1H), 5.10-5.02 (m, 1H), 4.60-4.54 (m, 1H), 3.90-3.86(m, 1H), 3.79-3.74 (m, 1H), 1.32 (d, J=6.0 Hz, 6H). MS: Calcd.: 432.Found: [M+H]⁺ 433.

Example 13(R)-2-(3-(Aminomethyl)-5-fluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol

A solution of(R)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile(Example 11; 0.60 g, 1.44 mmol), conc. HCl (0.3 ml), and Pd (10 wt. %,dry basis, on activated carbon, 0.3 g) in MeOH (8 ml) was flushed withN₂, evacuated, and then placed under of H₂ (40 psi) for 6 hrs. Thereaction was then evacuated, flushed with N₂, filtered, washed with MeOH(3×30 ml), and concentrated. The resulting solid was dissolved in themixture of DCM-MeOH (50:1, 100 ml) and treated with a saturated aqueousNa₂CO₃ solution (100 ml). The resulting mixture was shaken vigorouslyfor 30 min and allowed to separate. The aqueous layer was extracted withDCM (3×100 ml). The combined organic layers were dried, filtered andconcentrated. The resulting solid was purified by reverse-phase columnchromatography (5-50% CH₃CN in H₂O over 400 ml) to give the titlecompound (0.40 g, 66%). ¹H NMR (400 MHz, CD₃OD) δ 7.47-7.44 (m, 2H),7.37 (d, J=10.7 Hz, 1H), 7.06-7.02 (m, 2H), 5.10-5.06 (m, 1H), 4.57-4.51(m, 1H), 4.28 (d, J=14.2 Hz, 1H), 4.07 (d, J=14.2 Hz, 1H), 3.92-3.80 (m,2H), 1.32 (d, J=3.7 Hz, 6H). MS: Calcd.: 418. Found: [M+H]⁺ 419.

Example 14(R)—N-((5-Fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)pyridin-3-yl)methyl)acetamide

(R)-2-(3-(Aminomethyl)-5-fluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol(Example 13; 0.175 g, 0.42 mmol) and acetic acid loaded TFP resin (1.4mmol/g loading, 0.42 mmol) were placed in a THF-DCM solution (1:1, 5 ml)at 0° C. The resulting solution was shaken vigorously at 0° C. for 45min and filtered. The resulting resin was washed with a THF-DCM solution(1:1, 3×5 ml for 30 min. each). The resulting organic layers werecombined and concentrated. The resulting solid was purified byreverse-phase column chromatography (5-50% CH₃CN in H₂O over 400 ml) togive the title compound (0.075 g, 39%). ¹H NMR (400 MHz, CD₃OD) δ7.42-7.39 (m, 2H), 7.17 (d, J=10.7 Hz, 1H), 7.05-7.01 (m, 2H), 5.26 (s,1H), 5.02-4.95 (m, 1H), 4.55-4.53 (m, 1H), 4.36 (d, J=15.0 Hz, 1H), 4.22(d, J=15.0 Hz, 1H), 3.84-3.72 (m, 2H), 2.01 (s, 3H), 1.31 (d, J=6.0 Hz,6H). MS: Calcd.: 460. Found: [M+H]⁺ 461.

Example 15(R)—N-((5-Fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)pyridin-3-yl)methyl)methanesulfonamide

A round bottom flask was charged with(R)-2-(3-(aminomethyl)-5-fluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol(Example 13; 0.10 g, 0.24 mmol), methanesulfonic acid loaded TFP resin(0.9 mmol/g loading, 0.24 mmol), DIEA (0.062 g, 0.48 mmol), DMAP (0.032g, 0.26 mmol), and THF (5 ml). The resulting suspension was shakenvigorously at 60° C. for 8 hrs and filtered. The resulting resin waswashed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). Theresulting organic layers were combined and concentrated. The resultingsolid was purified by reverse-phase column chromatography (5-50% CH₃CNin H₂O over 400 ml) to give the title compound (0.075 g, 63%). ¹H NMR(400 MHz, CD₃OD) δ 7.48-7.45 (m, 2H), 7.20 (d, J=10.9 Hz, 1H), 7.05-7.01(m, 2H), 5.30 (s, 1H), 5.04-5.01 (m, 1H), 4.56-4.53 (m, 1H), 4.20 (d,J=14.4 Hz, 1H), 4.12 (d, J=14.4 Hz, 1H), 3.86-3.73 (m, 2H), 3.01 (s,3H), 1.32 (d, J=6.0 Hz, 3H). MS: Calcd.: 496. Found: [M+H]⁺ 497.

Example 16(S)-5-Fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile

2-Chloro-5-fluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile(Method 2; 1.4 g, 5.0 mmol) and (S)-1-(4-fluorophenyl)ethanamine (1.0 g,9.0 mmol) were added to a solution of n-BuOH (8 ml) and DIEA (0.8 g, 6.0mmol) in a sealed tube. The reaction was heated to 135° C. for 48 hrs,cooled to 25° C., and concentrated. The resulting residue was purifiedby column chromatography (DCM-MeOH=80:1) to give the title compound(0.90 g, 48%). ¹H NMR (400 MHz, CD₃OD) δ 7.43 (d, J=10.5 Hz, 1H),7.39-7.35 (m, 2H), 7.04-6.99 (m, 2H), 5.47 (s, 1H), 5.12-5.11 (m, 1H),4.60-4.51 (m, 1H), 1.56 (d, J=7.0 Hz, 3H), 1.33-1.30 (m, 6H). MS:Calcd.: 398. Found: [M+H]⁺ 399.

Example 17(S)-5-Fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinamide

(S)-5-Fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile(Example 16; 0.15 g, 0.38 mmol), was placed in MeOH (7 ml) at 25° C. A25% aqueous solution (0.4 ml) of KOH (0.11 g, 1.9 mmol) was then added,followed by the addition of 0.1 ml of 30% H₂O₂. The resulting dark redsolution was heated to 65° C. for 1 h, cooled to 25° C., andconcentrated. The resulting residue was dissolved in EtOAc (50 ml),washed with water (30 ml), dried, filtered, and concentrated. Theresulting solid was purified by column chromatography (DCM-MeOH=25:1) togive the title compound (0.044 g, 28%). ¹H NMR (400 MHz, CD₃OD) δ 7.75(d, J=11.7 Hz, 1H), 7.39-7.36 (m, 2H), 7.04-7.00 (m, 2H), 5.37 (s, 1H),5.11-5.00 (m, 1H), 4.61-4.52 (m, 1H), 1.53 (d, J=7.0 Hz, 3H), 1.31 (m,6H). MS: Calcd.: 416. Found: [M+H]⁺ 417.

Example 18(S)-3-(Aminomethyl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)-N⁶-(5-isopropoxy-1H-pyrazol-3-yl)pyridine-2,6-diamine

The mixture of(S)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile (Example 16; 0.90 g, 2.26 mmol), conc. HCl(0.3 ml), and Pd (10 wt. %, dry basis, on activated carbon, 0.55 g) inMeOH (20 ml) was flushed with N₂, evacuated, and then placed under H₂(40 psi) for 6 hrs. The reaction was then evacuated, flushed with N₂,filtered, washed with MeOH (3×30 ml), and concentrated. The resultingsolid was dissolved in the mixture of DCM-MeOH (50:1, 100 ml) andtreated with a saturated aqueous Na₂CO₃ solution (100 ml). The mixturewas shaken vigorously for 30 min and allowed to separate. The aqueouslayer was extracted with DCM (3×100 ml). The combined organic layerswere dried, filtered and concentrated. The resulting solid was purifiedby reverse-phase column chromatography (5-50% CH₃CN in H₂O over 400 ml)to give the title compound (0.7 g, 77%). ¹H NMR (400 MHz, CD₃OD) δ7.45-7.41 (m, 2H), 7.35 (d, J=10.9 Hz, 1H), 7.03-6.99 (m, 2H), 5.35 (s,1H), 5.09-5.04 (m, 1H), 4.55-4.49 (m, 1H), 4.18 (d, J=14.2 Hz, 1H), 4.08(d, J=14.2 Hz, 1H), 1.59 (d, J=6.8 Hz, 3H), 1.31 (d, J=8.3 Hz, 6H). MS:Calcd.: 402. Found: [M+H]⁺ 403.

Example 19(S)—N-((5-Fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)pyridin-3-yl)methyl)acetamide

(S)-3-(Aminomethyl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)-N⁶-(5-isopropoxy-1H-pyrazol-3-yl)pyridine-2,6-diamine (Example 18; 0.20 g, 0.49 mmol) and aceticacid loaded TFP resin (1.4 mmol/g loading, 0.49 mmol) were placed in aTHF-DCM solution (1:1, 6 ml) at 0° C. The resulting solution was shakenvigorously at 0° C. for 45 min and filtered. The resulting resin waswashed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). Theresulting organic layers were combined and concentrated. The resultingsolid was purified by reverse-phase column chromatography (5-50% CH₃CNin H₂O over 400 ml) to give the title compound (0.010 g, 49%). ¹H NMR(400 MHz, CD₃OD) δ 7.37-7.34 (m, 2H), 7.14 (d, J=10.9 Hz, 1H), 7.02-6.98(m, 2H), 5.25 (s, 1H), 4.96-4.95 (m, 1H), 4.55-4.52 (m, 1H), 4.30 (d,J=14.8 Hz, 1H), 4.21 (d, J=14.8 Hz, 1H), 2.01 (s, 3H), 1.51 (d, J=6.8Hz, 3H), 1.31 (d, J=6.0 Hz, 6H). MS: Calcd.: 444. Found: [M+H]⁺ 445.

Example 20(S)—N-((5-Fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)pyridin-3-yl)methyl)methanesulfonamide

A round bottom flask was charged with(S)-3-(aminomethyl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)-N⁶-(5-isopropoxy-1H-pyrazol-3-yl)pyridine-2,6-diamine(Example 18; 0.10 g, 0.25 mmol), methanesulfonic acid loaded TFP resin(0.9 mmol/g loading, 0.25 mmol), DIEA (0.064 g, 0.50 mmol), DMAP (0.033g, 0.27 mmol), and THF (5 ml). The resulting suspension was shakenvigorously at 60° C. for 8 hrs and filtered. The resulting resin waswashed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). Theresulting organic layers were combined and concentrated. The resultingsolid was purified by reverse-phase column chromatography (5-50% CH₃CNin H₂O over 400 ml) to give (0.82 g, 67%). ¹H NMR (400 MHz, CD₃OD) δ7.44-7.41 (m, 2H), 7.17 (d, J=10.7 Hz, 1H), 7.02-6.97 (m, 2H), 5.26 (s,1H), 5.01-4.99 (m, 1H), 4.56-4.53 (m, 1H), 4.16-4.08 (m, 1H), 3.01 (s,3H), 1.52 (d, J=7.0 Hz, 3H), 1.31 (d, J=6.0 Hz, 6H). MS: Calcd.: 480.Found: [M+H]⁺ 481.

Example 21(S)-3,5-Dichloro-N²-(5-cyclopropyl-1H-pyrazol-3-yl)-N⁶-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine

3,5,6-Trichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyridin-2-amine (Method3; 0.05 g, 0.2 mmol) and (S)-1-(4-fluorophenyl)ethanamine (0.05 g, 0.4mmol) were dissolved in NMP (2 ml) with DIEA (0.03 g, 0.22 mmol). Thereaction was heated in a microwave at 200° C. for 30 min. The reactionwas cooled to 25° C., quenched with water (10 ml), and extracted withMTBE (4×30 ml). The combined organic fractions were then dried,filtered, and concentrated. The resulting solid was purified byreverse-phase column chromatography (5-50% CH₃CN in H₂O over 400 ml) togive the title compound (0.008 g, 11%). ¹H NMR (400 MHz, CD₃OD) δ 7.41(s, 1H), 7.33-7.30 (m, 2H), 7.02-6.98 (m, 2H), 6.03 (s, 3H), 5.17 (q,J=6.8 Hz, 1H), 2.02-1.98 (m, 1H), 1.59 (d, J=6.8 Hz, 3H), 1.21-1.65 (m,2H), 0.86-0.82 (m, 2H). MS: Calcd.: 406. Found: [M+H]⁺ 407.

Example 22N-(5-Cyclopropyl-1H-pyrazol-3-yl)-N′-[(1S)-1-(4-fluorophenyl)ethyl]pyridine-2,6-diamine

tert-Butyl5-cyclopropyl-3-[(6-{[(is)-1-(4-fluorophenyl)ethyl]amino}pyridin-2-yl)amino]-1H-pyrazole-1-carboxylate(Method 21; 146 mg) was dissolved in a solution of hydrogen chloride inether (2.0 M, 2 ml, 4 mmol) and the reaction mixture was stirred at roomtemperature for 4 hours. The solvent was removed and semi-prep HPLC(Gilson) purification gave the title compound (37 mg, 25%). ¹H NMR(CDCl₃) δ 0.55 (m, 2H), 0.70 (m, 2H), 1.35 (m, 3H), 1.65 (m, 1H), 4.53(m, 2H), 4.91 (br s, 1H), 6.10 (br s, 1H), 6.70 (m, 1H), 7.00 (m, 2H),7.25 (m, 3H).

Example 23(S)-2-Amino-N-((6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)pyridin-3-yl)methyl)acetamide

To a solution of tert-butyl(2-{[(6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoro-2-{[(1S)-1-(4-fluorophenyl)ethyl]amino}pyridin-3-yl)methyl]amino}-2-oxoethyl)carbamate(Method 22; 0.035 g, 0.065 mmol) in dioxane (4 ml), was added anHCl/dioxane solution (4.0 M, 30 eq.). The resulting solution was stirredat 25° C. for 3 hrs. The reaction was then concentrated, re-dissolved inMeOH (0.5 ml), and quickly treated with ether (50 ml). The resultingsolid was collected to give the HCl salt of the title compound (0.025 g,87%). ¹H NMR (400 MHz, CD₃OD) δ 7.60 (d, J=10.7 Hz, 1H), 7.47-7.44 (m,2H), 7.07-7.03 (m, 2H), 5.78 (s, 1H), 5.04 (q, J=6.6 Hz, 1H), 4.43-4.40(m, 2H), 3.79 (s, 2H), 2.01-1.96 (m, 1H), 1.66 (d, J=6.6 Hz, 3H),1.17-1.13 (m, 2H), 0.82-0.81 (m, 2H). MS: Calcd.: 441. Found: [M+H]⁺442.

Example 24N-((6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-((S)-1-(4-fluorophenyl)ethylamino)pyridin-3-ylmethyl)-5-oxopyrrolidine-2-carboxamide

A round bottom flask was charged with(S)-3-(aminomethyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine(Example 3; 0.08 g, 0.2 mmol), 5-oxopyrrolidine-2-carboxylic acid loadedTFP resin (1.4 mmol/g loading, 0.2 mmol), and a THF-DCM solution (3 ml)at 0° C. The resulting solution was shaken vigorously at 0° C. for 45min and filtered. The resulting resin was washed with a THF-DCM solution(1:1, 3×5 ml for 30 min. each). The resulting organic layers werecombined and concentrated. The resulting solid was purified byreverse-phase column chromatography (5-50% CH₃CN in H₂O over 400 ml) togive the title compound (0.013 g, 10%). ¹H NMR (400 MHz, CD₃OD) δ7.41-7.32 (m, 2H), 7.21-7.13 (m, 1H), 7.05-6.97 (m, 2H), 6.05 (s, 1H),5.21-5.02 (m, 1H), 4.34-4.19 (m, 3H), 2.44-2.28 (m, 3H), 2.11-1.98 (m,1H), 1.88-1.81 (m, 1H), 1.51 (d, J=5.2 Hz, 3H), 0.99-0.86 (m, 2H),0.69-0.61 (m, 2H). MS: Calcd.: 495 Found: [M+H]⁺ 496.

Example 25N⁴-(5-Cyclopropyl-1H-pyrazol-3-yl)-N²-[(S)-1-(4-fluoro-phenyl)-ethyl]-pyridine-2,4-diamine

A mixture of(2-chloro-pyridin-4-yl)-(5-cyclopropyl-1H-pyrazole-3-yl)-amine (Method4; 0.116 g, 0.49 mmol), DIEA (0.20 ml, 1.18 mmol), and(S)-1-(4-fluoro-phenyl)-ethylamine (1.0 ml, 7.4 mmol) was heated to 160°C. in a sealed tube for 2 days. The reaction mixture was concentratedunder reduced pressure and purified by reverse-phase prep HPLC (column:mC-PACK-ODS-AQ, 250×20 nm, 3.0×50 mm; 5-95% gradient MeCN (0.05% TFA) inwater (0.1% TFA); flow rate: 10.0 ml/min). ¹H NMR (400 MHz) δ 0.696 (m,2H), 0.958 (m, 2H), 1.49 (m, 4H), 4.75 (q, 1H), 5.60 (s, 1H), 7.19 (t,2H), 7.29 (t, 1H), 7.42 (t, 3H), 7.6 (s, 1H), 9.89 (s, 1H). MS: Calcd.:337. Found: [M+H]⁺ 338.

Example 26(S)—N⁶-(5-Cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenol)ethyl)-3-nitropyridine-2,6-diamine

A mixture of(S)-6-chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method5; 1.74 g, 5.88 mmol), 5-cyclopropyl-1H-pyrazol-3-amine (0.91 g, 7.36mmol), and DIEA (1.28 ml, 7.36 mmol) in n-BuOH (10 ml) was heated in asealed tube at 160° C. for 60 hrs. The solvent was removed under reducedpressure and the residue was purified by chromatography(hexane-EtOAc=1:1) to give the title compound as a yellow solid (1.35 g,60%). ¹H NMR (400 MHz) δ 12.15 (s, 1H), 10.43 (br, 1H), 9.19 (br, 1H),8.12 (d, J=9.2 Hz, 1H), 7.45 (m, 2H), 7.17 (m, 2H), 6.25 (br, 1H), 6.14(br, 1H), 5.45 (m, 1H), 1.87 (m, 1H), 1.60 (d, J=6.8 Hz, 3H), 0.95 (m,2H), 0.65 (m, 2H). MS: Calcd.: 382. Found: [M+H]⁺ 383.

Examples 27-30

Following a similar procedure to Example 26, the following compoundswere synthesized from a chloronitropyridine by reacting it with anamine.

Ex Product NMR/MS Amine SM 27 N⁶-(5- (400 MHz) 12.10 (br s, 1H), 5-Method 6 Cyclopropyl- 10.40 (br s, 1H), 9.43 (br, 1H), 8.09 (d, J = 6.8Hz, cyclopropyl- 1H-pyrazol-3- 1H), 7.37 (m, 2H), 1H-pyrazol-3-yl)-N²-(4- 7.15 (m, 2H), 6.24 (br s, 1H), 6.04 (br s, aminefluorobenzyl)- 1H), 4.80 (d, J = 5.6 Hz, 2H), 3-nitropyridine- 1.772 (m,1H), 0.85 (m, 2H), 2,6-diamine 0.46 (m, 2H). MS: Calcd.: 368; Found:[M + H]⁺ 369 28 (2R)-2-({6-[(5- (400 MHz) 12.10 (s, 1H), 5- Method 7Cyclopropyl- 10.39 (br s, 1H), 9.57 (br s, 1H), 8.11 (d, cyclopropyl-1H-pyrazol-3- J = 9.2 Hz, 1H), 7.28 (m, 2H), 1H-pyrazol-3- yl)amino]-3-7.15 (m, 2H), 6.23 (br s, 1H), 5.76 (s, amine nitropyridin-2- 1H), 5.35(br s, 1H), 5.19 (t, J = 4.8 Hz, yl}amino)-2-(4- 1H), 3.86 (m, 1H),fluorophenyl)ethanol 3.75 (m, 1H), 1.87 (m, 1H), 0.95 (m, 2H), 0.64 (m,2H). MS: Calcd.: 398; Found: [M + H]⁺ 399 29 2-({6-[(5- (400 MHz) 11.94(s, 1H), 5- Method 8 Cyclopropyl- 10.15 (br s, 1H), 9.85 (s, 1H), 8.12(d, J = 9.2 Hz, cyclopropyl- 1H-pyrazol-3- 1H), 7.40 (m, 2H),1H-pyrazol-3- yl)amino]-3- 7.13 (m, 2H), 6.19 (br s, 1H), 2.86 (br s,amine nitropyridin-2- 2H), 4.44 (m, 4H), 1.65 (m, 1H), yl}amino)-2-(4-0.87 (m, 2H), 0.47 (m, 2H). MS: fluorophenyl)propane- Calcd.: 428;Found: [M + H]⁺ 429. 1,3-diol 30 N⁶-(5- MS: Calcd.: 382; Found: [M + H]⁺5- Method 9 Cyclopropyl- 383. cyclopropyl- 1H-pyrazol-3- 1H-pyrazol-3-yl)-N²-[(1R)-1- amine (4- fluorophenyl) ethyl]-3- nitropyridine-2,6-diamine

Example 31(S)—N⁶-(5-Cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine

To a suspension of(S)—N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)-3-nitropyridine-2,6-diamine(Example 26; 0.40 g, 1.05 mmol) and zinc dust (0.342 g, 5.23 mmol) inMeOH-THF (1:1, 16 ml) was slowly added a saturated aqueous ammoniumchloride solution (2.5 ml). The mixture was stirred at 25° C. for 1 hr,then treated with saturated ammonium acetate solution (4 ml). Theresulting mixture was stirred for another 30 min. The Zn dust wasremoved by filtration and the cake was washed with EtOAc (20 ml). Theorganic layer was separated, washed with brine (10 ml), and dried overNa₂SO₄. Removal of the solvent gave the title compound at quantitativeyield. ¹H NMR (400 MHz) δ 11.5 (br, 1H), 7.98 (br, 1H), 7.43 (m, 2H),7.07 (m, 2H), 6.67 (d, J=8 Hz, 1H), 6.09 (s, 1H), 5.63-5.70 (m, 2H),5.19 (m, 1H), 4.04 (br, 2H), 1.77 (m, 1H), 1.46 (d, J=6.8 Hz, 3H), 0.85(m, 2H), 0.59 (m, 2H). MS: Calcd.: 352. Found: [M+H]⁺ 353.

Examples 32-35

Following a similar procedure to Example 31, the following compoundswere synthesized from a nitropyridine by reacting it with zinc dust.

Ex Product MS SM 32 N⁶-(5-Cyclopropyl-1H-pyrazol-3-yl)-N²-(4- Calcd.:338; Found: Example fluorobenzyl)pyridine-2,3,6-triamine [M + H]⁺ 339 2733 (2R)-2-({3-Amino-6-[(5-cyclopropyl-1H-pyrazol-3- Calcd.: 368; Found:Example yl)amino]pyridin-2-yl}amino)-2-(4- [M + H]⁺ 369 28fluorophenyl)ethanol 34 2-({3-Amino-6-[(5-cyclopropyl-1H-pyrazol-3-Calcd.: 398; Found: Example yl)amino]pyridin-2-yl}amino)-2-(4- [M + H]⁺399 29 fluorophenyl)propane-1,3-diol 35N⁶-(5-Cyclopropyl-1H-pyrazol-3-yl)-N²-[(1R)-1-(4- Calcd.: 352; Found:Example fluorophenyl)ethyl]pyridine-2,3,6-triamine [M + H]⁺ 353 30

Example 36(S)-3-Chloro-N²-(5-cyclopropyl-1H-pyrazol-3-yl)-N⁶-(1-(4-fluorophenyl)ethyl)-5-nitropyridin-2,6-diamine

A mixture of(S)-5,6-chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine(Method 13; 0.61 g, 79% pure, 1.46 mmol),5-cyclopropyl-1H-pyrazol-3-amine (0.27 g, 2.19 mmol), and DIEA (0.38 ml,2.19 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 100° C. for48 hours. The solvent was removed under reduced pressure and the residuewas purified by column chromatography (hexane:EtOAc=2:1) to give thetitle compound as a yellow solid (0.57 g, 94%). NMR (400 MHz) 12.34 (s,1H), 9.34 (s, 1H), 8.93 (d, J=7.6 Hz, 1H), 8.26 (s, 1H), 7.32 (m, 2H),7.12 (m, 2H), 6.01 (s, 1H), 5.29 (m, 1H), 1.91 (m, 1H), 1.56 (d, J=7.2Hz, 3H), 0.96 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 416. Found: [M+H]⁺ 417.

Examples 37-40

Following a similar procedure to Example 36, the following compoundswere synthesized from a chloronitropyridine by reacting it with anamine.

Ex Product NMR/MS Amine SM 37 (2R)-2-({5-Chloro-6- (400 MHz) 12.28 (s,1H), 9.33 (d, J = 7.6 Hz, 5- Method [(5-cyclopropyl-1H- 1H), 9.28 (s,1H), 8.27 (s, 1H), cyclopropyl- 14 pyrazol-3-yl)amino]- 7.30 (m, 2H),7.13 (m, 1H), 5.94 (s, 1H- 3-nitropyridin-2- 1H), 5.22 (br s, 2H),3.84-3.73 (m, pyrazol-3- yl}amino)-2-(4- 2H), 1.90 (m, 1H), 0.97 (m,2H), amine fluorophenyl)ethanol 0.68 (m, 2H). MS: Calcd.: 432; Found:[M + H]⁺ 433 38 (2R)-2-({5-Chloro-6- (400 MHz) 12.23 (s, 1H), 9.35 (d, J= 7.2 Hz, 5-methyl- Method [(5-methyl-1H- 1H), 9.30 (s, 1H), 8.27 (s,1H), 1H-pyrazol- 14 pyrazol-3-yl)amino]- 7.32 (m 2H), 7.14 (m, 2H), 5.86(s, 3-amine 3-nitropyridin-2- 1H), 5.23 (t, J = 4.8 Hz, 1H), 5.18 (m,yl}amino)-2-(4- 1H), 3.81 (m, 1H), 3.74 (m, 1H), fluorophenyl)ethanol2.23 (s, 3H). MS: Calcd.: 406; Found: [M + H]⁺ 407 39(2R)-2-({6-[(5-tert- (400 MHz) 12.36 (s, 1H), 9.30 (s, 1H),5-tert-butyl- Method Butyl-1H-pyrazol-3- 9.29 (d, J = 7.6 Hz, 1H), 8.27(s, 1H), 1H-pyrazol- 14 yl)amino]-5-chloro-3- 7.26 (m 2H), 7.08 (m, 2H),6.18 (s, 3-amine nitropyridin-2- 1H), 5.29 (m, 1H), 5.21 (t, J = 4.8 Hz,yl}amino)-2-(4- 1H), 3.81 (m, 2H), 1.28 (s, 9H). MS:fluorophenyl)ethanol Calcd.: 448; Found: [M + H]⁺ 449 40 3-Chloro-N²-(5-(400 MHz) 12.33 (s, 1H), 9.32 (br s, (4- Method cyclopropyl-1H- 1H),8.26 (s, 1H), 8.20 (br s, 1H), fluorophenyl) 15 pyrazol-3-yl)-N⁶-(4-7.53 (m, 2H), 7.11 (m, 1H), 5.96 (s, 1H), methanamine fluorobenzyl)-5-4.69 (d, J = 6.0 Hz, 2H), 1.79 (m, 1H), nitropyridine-2,6- 0.87 (m, 2H),0.47 (m, 2H). sMS: diamine Calcd.: 402; Found: [M + H]⁺ 403

Example 41(S)-5-Chloro-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine

To a suspension of(S)-3-chloro-N²-(5-cyclopropyl-1H-pyrazol-3-yl)-N⁶-(1-(4-fluorophenyl)ethyl)-5-nitropyridin-2,6-diamine(Example 36; 0.57 g, 1.37 mmol) and zinc dust (0.447 g, 6.84 mmol) inMeOH:THF (1:1, 24 ml) was slowly added saturated ammonium chloridesolution (3.5 ml). The reaction mixture was stirred at 25° C. for 2hours, followed by addition of saturated ammonium acetate solution (5ml). The resulting mixture was stirred for another 30 minutes. Zn dustwas removed by filtration and washed with EtOAc (20 ml). The organiclayer was separated, washed with brine (10 ml), dried over Na₂SO₄ andthe solvent removed to give the title compound. MS: Calcd.: 386. Found:[M+H]⁺ 387.

Examples 42-45

Following a similar procedure to Example 41, the following compoundswere synthesized from a nitropyridine by reacting it with zinc dust.

Ex Product NMR/MS SM 42 (2R)-2-({3-Amino-5-chloro-6-[(5- MS: Calcd.:402; Example cyclopropyl-1H-pyrazol-3- Found: [M + H]⁺ 37yl)amino]pyridin-2-yl}amino)- 403 2-(4-fluorophenyl)ethanol 43(2R)-2-({3-Amino-5-chloro-6- MS: Calcd.: 376; Example[(5-methyl-1H-pyrazol-3- Found: [M + H]⁺ 38yl)amino]pyridin-2-yl}amino)-2- 377 (4-fluorophenyl)ethanol 44(2R)-2-({3-Amino-6-[(5-tert-butyl- MS: Calcd.: 418; Example1H-pyrazol-3-yl)amino]-5- Found: [M + H]⁺ 39chloropyridin-2-yl}amino)-2-(4- 419 fluorophenyl)ethanol 455-Chloro-N⁶-(5-cyclopropyl-1H- MS: Calcd.: 372; Examplepyrazol-3-yl)-N²-(4- Found: [M + H]⁺ 40fluorobenzyl)pyridine-2,3,6-triamine 373

Example 46(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinic acid

(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinamide(Example 2; 1.0 g, 2.5 mmol) was dissolved in a 10% aqueous EtOHsolution (10 ml) at 25° C., followed by addition of solid KOH (2.8 g,50.0 mmol). The reaction solution was heated to 95° C. for 4 days,cooled to 25° C., and extracted with DCM (2×50 ml). The aqueous layerwas then acidified to pH 3. The resulting solid (0.55 g), was collectedby filtration and dried under vacuum to give the title compound. MS:Calcd.: 399. Found: [M+H]⁺ 400.

Example 47(S)—N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-N⁶-(1-(4-fluorophenyl)ethyl)-3-nitropyridine-2,6-diamine

A mixture of6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine(Method 16; 0.30 g, 1.07 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.23g, 1.61 mmol), and DIEA (0.23 ml, 1.34 mmol) in n-BuOH (5 ml) was heatedin a sealed tube at 165° C. for 18 hrs. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.41 g,99%). ¹H NMR (400 MHz) δ 12.22 (s, 1H), 10.98 (s, 1H), 8.70 (d, J=7.2Hz, 1H), 8.10 (d, J=9.2 Hz, 1H), 7.39 (m, 2H), 7.18 (m, 2H), 6.22 (d,J=9.2 Hz, 1H), 6.17 (s, 1H), 5.27 (m, 1H), 1.89 (m, 1H), 1.52 (d, J=6.4Hz, 3H), 0.95 (m, 2H), 0.64 (m 2H). MS: Calcd.: 382. Found: [M+H]⁺ 383.

Examples 48-50

Following a similar procedure to Example 47, the following compoundswere synthesized from6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine(Method 16) and the appropriate amine.

Ex. Product NMR/MS Amine 48 N⁶-(4-Fluorobenzyl)- (400 MHz) 12.24 (s,1H), 10.98 (s, 1H), (4- N²-(5-cyclopropyl-1H- 8.29 (br s, 1H), 8.11 (d,J = 9.2 Hz, 1H), 7.36 (m, fluorobenzyl) pyrazol-3-yl)-3- 2H), 7.18 (m,2H), 6.20 (d, J = 9.6 Hz, 1H), amine nitropyridine-2,6- 6.19 (s, 1H),4.66 (d, J = 5.2 Hz, 2H), diamine 1.79 (m, 1H), 0.86 (m, 2H), 0.45 (m,2H). MS: Calcd.: 368; Found: [M + H]⁺ 369 49 (R)-2-[6-(5- (400 MHz)12.21 (s, 1H), 10.97 (s, 1H), (R)-2-amino- Cyclopropyl-1H- 8.74 (d, J =7.6 Hz, 1H), 8.09 (d, J = 9.6 Hz, 1H), 2-(4- pyrazol-3-ylamino)-5- 7.38(m, 2H), 7.18 (m, 2H), 6.31 (d, J = 9.2 Hz, fluorophenyl)nitropyridin-2- 1H), 6.20 (s, 1H), 5.21 (d, J = 5.6 Hz, ethanolylamino]-2-(4- 1H), 5.09 (t, J = 5.2 Hz, 1H), 3.64-3.75 (m,fluorophenyl)ethanol 2H), 1.91 (m, 1H), 0.98 (m, 2H), 0.66 (m, 2H). MS:Calcd.: 398; Found: [M + H]⁺ 399. 50 2-[6-(5-Cyclopropyl- (400 MHz)12.02 (s, 1H), 10.95 (s, 1H), 2-amino-2-(4- 1H-pyrazol-3- 8.07 (d, J =9.2 Hz, 1H), 7.93 (s, 1H), 7.35 (m, fluorophenyl) ylamino)-5- 2H), 7.14(m, 2H), 6.48 (d, J = 9.2 Hz, 1H), propane-1,3- nitropyridin-2- 5.04 (s,1H), 4.81 (s, 2H), 4.04 (m, 2H), diol ylamino]-2-(4- 3.90 (m, 2H), 1.68(m, 1H), 0.90 (m, 2H), fluorophenyl)propane- 0.51 (m, 2H). MS: Calcd.:428; Found: [M + H]⁺ 1,3-diol 429.

Example 51(S)-3-Chloro-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-[1-(4-fluorophenyl)ethyl]-5-nitropyridin-2,6-diamine

A mixture of5,6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridine-2-amine(Method 17; 0.26 g, 0.83 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (0.17g, 1.25 mmol), and DIEA (0.22 ml, 1.25 mmol) in n-BuOH (5 ml) was heatedin a sealed tube at 165° C. for 3 hours. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane:EtOAc=1:1) to give the title compound as a yellow solid (0.34 g,99%). NMR (400 MHz) 12.29 (s, 1H), 10.68 (s, 1H), 8.27 (s, 1H), 8.24 (d,J=8.0 Hz, 1H), 7.39 (m, 2H), 7.16 (m, 2H), 6.11 (s, 1H), 5.42 (m, 1H),1.89 (m, 1H), 1.60 (d, J=7.2 Hz, 3H), 0.95 (m, 2H), 0.61 (m, 2H). MS:Calcd.: 416. Found: [M+H]⁺ 417.

Examples 52-54

Following a similar procedure to Example 51, the following compoundswere synthesized from the appropriate starting material and amine.

Ex. Product NMR/MS SM Amine 2 52 N²-(4-Fluorobenzyl)- (400 MHz) 12.29(s, 1H), Method (4-fluoro- 3-chloro-N⁶-(5- 10.73 (s, 1H), 8.70 (t, J =6.0 Hz, 1H), 17 phenyl)methanamine cyclopropyl-1H- 8.12 (b, 1H), 7.30(m, 2H), pyrazol-3-yl)-5- 7.16 (m, 2H), 6.02 (s, 1H), 4.71 (d, J = 6.0Hz, nitropyridin-2,6- 2H), 1.77 (m, 1H), diamine 0.86 (m, 2H), 0.41 (m,2H). MS: Calcd.: 402; Found: [M + H]⁺ 403. 53 (R)-2-[3-Chloro-6- (400MHz) 12.27 (s, 1H), Method 5- (5-cyclopropyl-1H- 10.70 (s, 1H), 8.29 (d,J = 1.6 Hz, 1H), 18 cyclopropyl- pyrazol-3-ylamino)- 8.03 (d, J = 7.6Hz, 1H), 7.39 (m, 1H-pyrazol-3- 5-nitropyridin-2- 2H), 7.14 (m, 2H),6.15 (s, 1H), amine ylamino]-2-(4- 5.31 (m, 1H), 5.13 (t, J = 4.8 Hz,fluorophenyl)ethanol 1H), 3.32-3.86 (m, 2H), 1.92 (m, 1H), 0.98 (m, 2H),0.68 (m, 2H). MS: Calcd.: 432; Found: [M + H]⁺ 433. 54(2R)-2-({3-Chloro-6- (400 MHz) 12.23 (s, 1H), Method 5-methyl-1H-[(5-methyl-1H- 10.69 (s, 1H), 8.30 (s, 1H), 8.00 (d, J = 7.6 Hz, 18pyrazol-3- pyrazol-3-yl)amino]- 1H), 7.41 (m 2H), amine5-nitropyridin-2- 7.17 (m, 2H), 6.12-5.26 (m, 1H), yl}amino)-2-(4- 5.13(t, J = 5.2 Hz, 1H), 3.73-3.86 (m, fluorophenyl)ethanol 2H), 2.25 (s,3H). MS: Calcd.: 406; Found: [M + H]⁺ 407

Example 55(S)—N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-N⁶-[1-(4-fluorophenyl)ethyl]pyridine-2,3,6-triamine

To a suspension of(S)—N²-(5-cyclopropyl-1H-pyrazol-3-yl)-N⁶-[1-(4-fluorophenyl)ethyl]-3-nitropyridine-2,6-diamine(Example 47; 0.26 g, 0.68 mmol) and zinc dust (0.223 g, 3.41 mmol) inMeOH:THF (1:1, 12 ml) was slowly added saturated ammonium chloridesolution (1.5 ml). The reaction mixture was stirred at 25° C. for 1hour, to which was then added saturated ammonium acetate solution (5ml). The resulting mixture was stirred for another 30 minutes. Zn dustwas removed by filtration and washed with EtOAc (20 ml). The organiclayer was separated, washed with brine (10 ml), dried over Na₂SO₄, andconcentrated to give the title compound.

Examples 56-62

Following a similar procedure to Example 55, the following compoundswere synthesized from a suitable nitro-pyridine.

Ex. Compound NMR/MS SM 56 N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-N⁶-(4- MS:Calcd.: 338; Example fluorobenzyl)pyridine-2,3,6-triamine Found: [M +H]⁺ 339 48 57 (2R)-2-({5-Amino-6-[(5-cyclopropyl-1H- MS: Calcd.: 368;Example pyrazol-3-yl)amino]pyridin-2-yl}amino)-2-(4- Found: [M + H]⁺ 36949 fluorophenyl)ethanol 58 2-({5-Amino-6-[(5-cyclopropyl-1H-pyrazol- MS:Calcd.: 398; Example 3-yl)amino]pyridin-2-yl}amino)-2-(4- Found: [M +H]⁺ 399 50 fluorophenyl)propane-1,3-diol 595-Chloro-N²-(5-cyclopropyl-1H-pyrazol-3- MS: Calcd.: 386; Exampleyl)-N⁶-[(1S)-1-(4- Found: [M + H]⁺ 387 51fluorophenyl)ethyl]pyridine-2,3,6-triamine 605-Chloro-N²-(5-cyclopropyl-1H-pyrazol-3- MS: Calcd.: 372; Exampleyl)-N⁶-(4-fluorobenzyl)pyridine-2,3,6- Found: [M + H]⁺ 373 52 triamine61 (2R)-2-({5-Amino-3-chloro-6-[(5- MS: Calcd.: 402; Examplecyclopropyl-1H-pyrazol-3-yl)amino]pyridin- Found: [M + H]⁺ 403 532-yl}amino)-2-(4-fluorophenyl)ethanol 62(2R)-2-({5-Amino-3-chloro-6-[(5-methyl-1H- MS: Calcd.: 376; Examplepyrazol-3-yl)amino]pyridin-2-yl}amino)-2-(4- Found: [M + H]⁺ 377 54fluorophenyl)ethanol

Example 63N-(5-Cyclopropyl-1H-pyrazol-3-yl)-N′-(4-fluorobenzyl)pyridine-2,6-diamine

To a flask was added Pd(OAc)₂ (22.4 mg, 0.1 mmol),(biphenyl-2-ylmethylene)bis(dimethylphosphine) (60 mg, 0.2 mmol) andsodium tert-butoxide (240 mg, 2.5 mmol). The flask was sealed andrefilled with N₂. To the mixture was added a solution of6-bromo-N-(4-fluorobenzyl)pyridin-2-amine (Method 19; 281 mg, 1.0 mmol)and 5-cyclopropyl-1H-pyrazol-3-amine (123 mg, 1.0 mmol) in toluene (5ml). The reaction mixture was heated at 110° C. overnight. The solventwas removed and EtOAc was added and the mixture was washed with brineand was concentrated. Semi-prep HPLC (Gilson) purification gave thetitle compound (6.4 mg, 2%). ¹H NMR (CDCl₃) δ 0.65 (m, 2H), 0.95 (m,2H), 1.80 (m, 1H), 4.43 (m, 2H), 4.91 (br s, 1H), 5.60 (br s, 1H), 5.80(m, 1H), 6.18 (m, 1H), 6.73 (m, 1H), 7.00 (m, 2H), 7.25 (m, 3H).

Example 64(S)-5-Chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-(1-(5-fluoropyridin-2-yl)ethylamino)nicotinonitrile

A solution of2,5-dichloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)nicotinonitrile(Method 43, 0.60 g, 2.04 mmol), DIEA (0.34 g, 2.65 mmol), and(S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 33; 0.90 g, 6.12 mmol) inn-BuOH was heated to 120° C. for 9 hours. The reaction was then cooledto room temperature, diluted with water (20 ml), and extracted with DCM(2×50 ml). The combined organic fractions were dried over Na₂SO₄,filtered, and then concentrated. The resulting oil was purified bycolumn chromatography (DCM-MeOH=100:1) to give the title compound (0.42g, 52%). ¹H NMR (400 MHz, CD₃OD) δ 8.42 (d, J=2.7 Hz, 1H), 7.61 (s, 1H),7.51-7.49 (m, 1H), 7.38-7.32 (m, 1H), 6.06 (br s, 1H), 5.28-5.22 (m,1H), 1.94-1.88 (m, 1H), 1.58 (d, J=6.9 Hz, 3H), 1.01 (br s, 2H),0.76-0.75 (m, 2H). MS: Calcd.: 397. Found: [M+H]⁺ 398.

Example 65(S)—N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-3-fluoro-N⁶-(1-(4-fluorophenyl)ethyl)-5-nitropyridine-2,6-diamine

To a solution of(S)-5,6-difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine(Method 23, 0.60 g, 2.0 mmol) in THF (10 ml) at room temperature wasadded 5-cyclopropyl -1H-pyrazol-3-amine (0.50 g, 4.0 mmol), and DIEA(0.26 g, 2.0 mmol). The reaction was then heated to 55° C. for 24 hours,cooled to room temperature, and quenched with water. The reaction wasthen extracted with DCM (2×75 ml), and the combined organic fractionswere dried over Na₂SO₄, filtered, and then concentrated. The resultingoil was purified by column chromatography (DCM-MeOH=100:1) to give thetitle compound (0.53 g, 66%). ¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, J=11.1Hz, 1H), 7.38-7.35 (m, 2H), 7.07-7.02 (m, 2H), 6.17 (s, 1H), 5.41-5.39(m, 1H), 1.93-1.87 (m, 1H), 1.61 (d, J=7.0 Hz, 3H), 1.02-1.00 (m, 2H),0.69-0.66 (m, 2H). MS: Calcd.: 400. Found: [M+H]⁺ 401.

Example 66(S)-3-Fluoro-N⁶-(1-(4-fluorophenyl)ethyl)-N²-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine

To a solution of(S)-5,6-difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine(Method 23; 0.60 g, 2.0 mmol) in THF (10 ml) at room temperature wasadded 5-isopropoxy -1H-pyrazol-3-amine (0.50 g, 3.0 mmol), and DIEA(0.29 g, 2.2 mmol). The reaction was then heated to 55° C. for 24 hours,cooled to room temperature, and quenched with water. The reaction wasthen extracted with DCM (2×75 ml), and the combined organic fractionswere dried over Na₂SO₄, filtered, and then concentrated. The resultingoil was purified by column chromatography (DCM-MeOH=100:1) to give thetitle compound (0.34 g, 40%). ¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, J=10.9Hz, 1H), 7.45-7.35 (m, 2H), 7.07-7.03 (m, 2H), 5.88-5.71 (m, 1H),5.48-5.30 (m, 1H), 4.58-4.29 (m, 1H), 1.68-1.56 (m, 3H), 1.34-1.28 (m,6H). MS: Calcd.: 418. Found: [M+H]⁺ 419.

Example 67(R)-2-(6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-3-nitropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol

To a solution of(S)-2-(5,6-difluoro-3-nitropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol(Method 25, 0.40 g, 1.3 mmol) in THF (10 ml) at room temperature wasadded 5-cyclopropyl-1H-pyrazol-3-amine (0.31 g, 2.6 mmol), and DIEA(0.18 g, 1.4 mmol). The reaction was then heated to 55° C. for 12 hours,cooled to room temperature, and quenched with water. The reaction wasthen extracted with DCM (2×75 ml), and the combined organic fractionswere dried over Na₂SO₄, filtered, and then concentrated. The resultingoil was purified by column chromatography (DCM-MeOH=100:1) to give thetitle compound (0.45 g, 85%). ¹H NMR (400 MHz, CDCl₃) δ 10.84 (s, 1H),8.02 (d, J=10.7 Hz, 1H), 7.35-7.31 (m, 2H), 7.10-7.06 (m, 2H), 6.21-6.19(m, 1H), 5.80 (br s, 1H), 4.07 (dd, J=11.3, 3.9 Hz, 1H), 3.99 (dd,J=11.3, 6.4 Hz, 1H), 1.88-1.86 (m, 1H), 1.62 (br s, 1H), 0.98-0.95 (m,2H), 0.70-0.68 (m, 2H). MS: Calcd.: 416. Found: [M+H]⁺ 417.

Example 68(R)-2-(5-Fluoro-6-(5-methyl-1H-pyrazol-3-ylamino)-3-nitropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol

To a solution of(S)-2-(5,6-difluoro-3-nitropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol(Method 25; 0.60 g, 1.9 mmol) in THF (10 ml) at room temperature wasadded 5-methyl-1H-pyrazol-3-amine (0.37 g, 3.8 mmol), and DIEA (0.27 g,2.1 mmol). The reaction was heated to 55° C. for 12 hours, cooled toroom temperature, and quenched with water. The reaction was thenextracted with DCM (2×75 ml), and the combined organic fractions weredried over Na₂SO₄, filtered, and then concentrated. The resulting oilwas purified by column chromatography (DCM-MeOH=100:1) to give the titlecompound (0.51 g, 68%). ¹H NMR (400 MHz, CDCl₃) δ 10.85 (br s, 1H), 8.02(d, J=10.5 Hz, 1H), 7.34-7.31 (m, 2H), 7.10-7.06 (m, 2H), 6.26-6.25 (m,1H), 5.86 (br s, 1H), 5.30-5.27 (m, 1H), 4.07 (dd, J=11.3 and 3.9 Hz,1H), 3.97 (dd, J=11.1, 6.2 Hz, 1H), 2.27 (s, 3H), 1.61 (br s, 1H). MS:Calcd.: 390. Found: [M+H]⁺ 391.

Example 69(S)-3-Chloro-N²-(1-(4-fluorophenol)ethyl)-N⁶-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine

A mixture of5,6-dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine(Method 26, 0.25 g, 0.75 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.13g, 0.90 mmol) and DIEA (0.16 ml, 0.94 mmol) in n-BuOH (3 ml) was heatedin a sealed tube at 145° C. for 4 hours. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.32 g,98%). ¹H NMR (400 MHz) δ 12.16 & 11.72 (s, 1H), 10.64 & 10.58 (s, 1H),8.30 (m, 2H), 7.37 & 7.31 (m, 2H), 7.16 & 7.08 (m, 2H), 5.81 & 5.71 (s,1H), 5.48 & 5.33 (m, 1H), 4.60 & 4.21 (m, 1H), 1.61 & 1.57 (d, J=6.8 Hz,3H), 1.25 (m, 6H). MS: Calcd.: 434. Found: [M+H]⁺ 435.

Example 70(S)-3-Chloro-N⁶-(1-(4-fluorophenyl)ethyl)-N²-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine

A mixture of3,6-dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridin-2-amine(Method 27, 0.25 g, 0.75 mmol), (s)-1-(4-fluoro-phenyl)-ethylamine (0.13g, 0.90 mmol) and DIEA (0.16 ml, 0.94 mmol) in n-BuOH (3 ml) was heatedin a sealed tube at 145° C. for 2 hours. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.32 g,98%). ¹H NMR (400 MHz) δ 12.22 & 11.40 (s, 1H), 9.74 & 9.37 (s, 1H),8.93 (d, J=7.6 Hz, 1H), 8.33 & 8.27 (s, 1H), 7.34 & 7.27 (m, 2H), 7.12 &7.05 (m, 2H), 5.75 & 5.62 (s, 1H), 5.35 & 5.25 (m, 1H), 4.66 & 4.03 (m,1H), 1.55 (d, J=6.4 Hz, 3H), 1.29 (d, J=6.0 Hz, 6H). MS: Calcd.: 434.Found: [M+H]⁺ 435.

Example 71(S)—N⁶-(1-(4-Fluorophenyl)ethyl)-N²-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridine-2,6-diamine

A mixture of6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Method28, 0.33 g, 1.1 mmol), (s)-1-(4-fluoro-phenyl)-ethylamine (0.16 g, 1.2mmol) and DIEA (0.21 ml, 1.2 mmol) in n-BuOH (3 ml) was heated in asealed tube at 165° C. for 4 hours. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.43 g,97%). ¹H NMR (400 MHz) δ 12.09, 12.05 & 11.64 (s, 1H), 10.94, 10.87 &10.72 (s, 1H), 8.98, 8.76 & 8.70 (d, J=7.6 Hz, 1H), 8.16 & 8.11 (d,J=9.6 Hz, 1H), 7.40-7.33 (m, 2H), 7.22-7.10 (m, 2H), 6.25 & 6.04 (d,J=9.6 Hz, 1H), 6.23 & 5.86 (d, J=13.6 Hz, 1H), 5.31, 5.21 & 4.89 (m,1H), 4.71, 4.59 & 4.27 (m, 1H), 1.52 (m, 3H), 1.26 (m, 6H). MS: Calcd.:400. Found: [M+H]⁺ 401.

Example 72(S)—N-((6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)pyridin-3-yl)methyl)-2-morpholinoacetamide

A solution of(S)-3-(aminomethyl)-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine(Example 3, 0.16 g, 0.42 mmol), 2-morpholinoacetic acid (0.06 g, 0.42mmol), HBTU (0.16 g, 0.42 mmol) and DIEA (0.16 g, 1.2 mmol) in DCM (3ml) was stirred at room temperature for 1 hour. The reaction was thenquenched with a saturated aqueous solution of NaHCO₃, and extracted withDCM (2×50 ml). The combined organic fractions were dried over Na₂SO₄,filtered, and then concentrated. The resulting oil was purified bycolumn chromatography (DCM-MeOH=100:1) to give the title compound (0.02g, 10%). ¹H NMR (400 MHz, CD₃OD) δ 7.35 (br s, 2H), 7.17 (br s, 1H),7.01-6.97 (m, 2H), 6.06 (br s, 1H), 5.16-4.99 (m, 1H), 4.30 (br s, 2H),3.68 (br s, 4H), 3.06 (br s, 2H), 2.48 (br s, 4H), 1.87-1.82 (m, 1H),1.51 (d, J=6.4 Hz, 3H), 0.91 (br s, 2H), 0.64 (br s, 2H). MS: Calcd.:511. Found: [M+H]⁺ 512.

Example 73(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde

(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile (Example 1, 0.4 g, 1.1 mmol) was dissolved inthe mixture pyridine-acetic acid-water (1:1:1, 18 ml total volume) atroom temperature, to which was added Raney nickel (0.09 g, 1.1 mmol).The reaction was purged with nitrogen, evacuated, and then placed underhydrogen filled balloon for 18 hours. The reaction mixture was flushedwith nitrogen, and filtered to remove the catalyst, which was washedwith MeOH (30 ml). The filtrate was then extracted with DCM (5×50 ml),washed with aq. NaHCO₃, and purified by reverse phase columnchromatography (5-30% ACN) to give the title compound (0.18 g, 45%). ¹HNMR (400 MHz, CD₃OD) δ 9.40 (s, 1H), 7.45 (d, J=10.4 Hz, 1H), 7.34-7.31(m, 2H), 7.05-7.01 (m, 2H), 6.11 (s, 1H), 5.26 (s, 1H), 1.92-1.86 (m,1H), 1.55 (d, J=7.0 Hz, 3H), 1.00-0.98 (m, 2H), 0.71-0.64 (m, 2H). MS:Calcd.: 383. Found: [M+H]⁺ 384.

Example 74(S)-(6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)pyridin-3-yl)methanol

To a solution of(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde(Example 73; 0.10 g, 0.26 mmol) in MeOH (5 ml) at 0° C. was added NaBH₄(0.012 g, 0.33 mmol). The reaction was stirred for 10 minutes, and thenquenched with water and extracted with DCM (2×20 ml). The combinedorganic fractions were dried over Na₂SO₄, filtered, and thenconcentrated. The resulting oil was purified by column chromatography(DCM-MeOH=100:1) to give the title compound (0.088 g, 88%). ¹H NMR (400MHz, CD₃OD) δ 7.42-7.39 (m, 2H), 7.16-7.01 (m, 1H), 7.01 (br s, 2H),6.06-5.41 (m, 1H), 5.19-5.02 (m, 1H), 4.52 (br s, 2H), 1.88-1.81 (m,1H), 1.53 (d, J=6.6 Hz, 3H), 0.97-0.91 (m, 2H), 0.65 (br s, 2H). MS:Calcd.: 385. Found: [M+H]⁺ 386.

Example 75(S)—N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-3-fluoro-N⁶-(1-(4-fluorophenyl)ethyl)-5-(morpholinomethyl)pyridine-2,6-diamine

To a solution of(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde(Example 73, 0.12 g, 0.31 mmol) in DCE (5 ml) was added morpholine (0.1g, 1.14 mmol) and NaBH(OAc)₃ (0.30 g, 1.5 mmol). The reaction was thenstirred for 2 days, quenched with aq. Na₂CO₃ (10 ml), and extracted withDCM (2×20 ml). The combined organic fractions were dried over Na₂SO₄,filtered, and then concentrated. The resulting oil was purified byreverse-phase column chromatography (5-35% ACN) to give the titlecompound (0.09 g, 67%). ¹H NMR (400 MHz, CD₃OD) δ 7.41 (br s, 2H),7.06-7.02 (m, 3H), 6.13 & 5.44 (s, 1H), 5.12 & 4.97 (s, 1H), 3.63 (br s,4H), 3.42 (br s, 2H), 2.41 (br s, 4H), 1.87-1.82 (m, 1H), 1.54 (d, J=6.5Hz, 3H), 0.96-0.90 (m, 2H), 0.65-0.64 (m, 2H). MS: Calcd.: 454. Found:[M+H]⁺ 455.

Example 76(R)-2-(4-Fluorophenyl)-2-(6-(5-methyl-1H-pyrazol-3-ylamino)-3-nitropyridin-2-ylamino)ethanol

A mixture of(R)-2-(6-chloro-3-nitropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol(Method 29, 0.36 g, 1.2 mmol), 5-methyl-1H-pyrazol-3-amine (0.14 g, 1.4mmol), and DIEA (0.25 ml, 1.4 mmol) in n-BuOH (5 ml) was heated in asealed tube at 90° C. for 6 days. The solvent was removed under reducedpressure and the residue was purified by column chromatography (EtOAc)to give the title compound as a yellow solid (0.31 g, 73%). ¹H NMR (400MHz) δ 12.06 (s, 1H), 10.40 (br, 1H), 9.58 (br, 1H), 8.11 (d, J=9.2 Hz,1H), 7.40 (m, 2H), 7.16 (m, 2H), 6.20 (br, 1H), 6.02 (s, 1H), 5.29 (br,1H), 5.24 (t, J=4.4 Hz, 1H), 3.85 (m, 1H), 3.74 (m, 1H), 2.20 (s, 3H).MS: Calcd.: 372. Found: [M+H]⁺ 373.

Example 77(S)—N²-(1-(4-Fluorophenyl)ethyl)-N⁶-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridine-2,6-diamine

A mixture of(S)-6-chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method30, 1.08 g, 3.7 mmol), 5-isopropoxy-1H-pyrazol-3-amine (0.57 g, 4.0mmol), and DIEA (0.80 ml, 4.6 mmol) in n-BuOH (10 ml) was heated in asealed tube at 115° C. for 72 hours. The solvent was removed underreduced pressure and the residue was purified by chromatography(hexane-EtOAc=3:1) to give the title compound as a yellow solid (0.32 g,22%). MS: Calcd.: 400. Found: [M+H]⁺ 401.

Example 78(R)-2-(4-Fluorophenyl)-2-(6-(5-isopropoxy-1H-pyrazol-3-ylamino)-5-nitropyridin-2-ylamino)ethanol

A mixture of6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Method28; 0.25 g, 0.84 mmol), (R)-2-amino-2-(4-fluorophenyl)ethanol (0.15 g,0.97 mmol) and DIEA (0.16 ml, 0.92 mmol) in n-BuOH (3 ml) was heated ina sealed tube at 165° C. for 4 hours. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane-EtOAc=1:2) to give the title compound as a yellow solid (0.30 g,87%). ¹H NMR (400 MHz) δ 12.12, 12.10 & 11.61 (s, 1H), 10.94, 10.89 &10.74 (s, 1H), 9.05, 8.82 & 8.73 (d, J=7.2 Hz, 1H), 8.13 & 8.11 (d,J=9.2 Hz, 1H), 7.45-7.32 (m, 2H), 7.20-7.10 (m, 2H), 6.32 & 6.07 (d,J=9.2 Hz, 1H), 5.90, 5.83 & 5.79 (s, 1H), 5.23, 5.12 & 4.78 (m, 2H),4.71, 4.64 & 4.37 (m, 1H), 3.69 (m. 2H), 1.34 & 1.29 (d, J=6.0 Hz, 6H).MS: Calcd.: 416. Found: [M+H]⁺ 417.

Example 79(S)—N-((6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)pyridin-3-yl)methyl)isoxazole-5-carboxamide

To a solution of(S)-3-(aminomethyl)-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine(Example 3, 0.08 g, 0.21 mmol) in DCM-THF mixture (1:1, 4 ml) at 0° C.was added 1.0 eq. of isoxazole-5-carboxylic acid loaded TFP resin. Theresulting mixture was stirred vigorously for 1 hour at 0° C., and thenfiltered. The remaining resin was then washed with DCM-THF (1:1, 2×10 mlportions) for 30 min, and then filtered. The combined filtrates wereconcentrated, and the resulting oil was purified by columnchromatography to give the title compound (3.4 mg, 4%). MS: Calcd.: 479.Found: [M+H]⁺ 480.

Example 80-103

The following compounds were prepared by the procedure similar to thatof Example 79 using(S)-3-(aminomethyl)-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine(Example 3) and a TFP resin loaded reagent.

Ex. Compound NMR and/or LC/MS TFP loaded resin 80(S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 488; benzoic acidpyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 489. (1-(4-fluorophenyl)ethylamino)pyridin-3- yl)methyl)benzamide 81(S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 489; pyridine-3-carboxylicpyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 490. acid(1-(4-fluorophenyl) ethylamino)pyridin-3- yl)methyl)nicotinamide 82(S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 489; pyridine-4-carboxylicpyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 490. acid(1-(4-fluorophenyl) ethylamino)pyridin-3- yl)methyl)isonicotinamide 83(S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 493; 5-methylisoxazole-4-pyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 494. carboxylic acid(1-(4-fluorophenyl) ethylamino)pyridin-3- yl)methyl)-5-methylisoxazole-4-carboxamide 84 (S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 494;thiophene-2- pyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 495.carboxylic acid (1-(4-fluorophenyl) ethylamino)pyridin-3-yl)methyl)thiophene-2- carboxamide 85 (S)—N-((6-(5-Cyclopropyl-1H- MS:Calcd.: 545; 4- pyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 546.(dimethylamino)phenyl (1-(4-fluorophenyl) acetic acidethylamino)pyridin-3- yl)methyl)-2-(4- (dimethylamino)phenyl)acetamide86 (S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 561;(isopropylmethanesulfonylamino) pyrazol-3-ylamino)-5-fluoro-2- Found:[M + H]⁺ 562. acetic (1-(4-fluorophenyl) acid ethylamino)pyridin-3-yl)methyl)-2-(N-(isopropyl)-N- methylsulfonamido)acetamide 87(S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 573; 1-methanesulfonylpyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 574. piperidine-4-(1-(4-fluorophenyl) carboxylic acid ethylamino)pyridin-3-yl)methyl)-1-(methylsulfonyl) piperidine-4-carboxamide 88(S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 532; 6-dimethylaminopyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 533. nicotinic acid(1-(4-fluorophenyl) ethylamino)pyridin-3- yl)methyl)-6-(dimethylamino)nicotinamide 89 (S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 574;(6-morpholin-4- pyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 575.yl)nicotinic acid (1-(4-fluorophenyl) ethylamino)pyridin-3-yl)methyl)-6-morpholino nicotinamide 90 (S)—N-((6-(5-Cyclopropyl-1H- MS:Calcd.: 503; (3-pyridyl)acetic acid pyrazol-3-ylamino)-5-fluoro-2-Found: [M + H]⁺ 504. (1-(4-fluorophenyl) ethylamino)pyridin-3-yl)methyl)-2-(pyridin-3-yl) acetamide 91 (S)—N-((6-(5-Cyclopropyl-1H- MS:Calcd.: 512; tetrahydrothiopyran- pyrazol-3-ylamino)-5-fluoro-2- Found:[M + H]⁺ 513. 4-carboxylic acid (1-(4-fluorophenyl)ethylamino)pyridin-3- yl)methyl)tetrahydro-2H- thiopyran-4-carboxamide92 (S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 508; 2-thiophene aceticpyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 509. acid(1-(4-fluorophenyl) ethylamino)pyridin-3- yl)methyl)-2-(thiophen-2-yl)acetamide 93 (S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 508;3-thiophene acetic pyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 509.acid (1-(4-fluorophenyl) ethylamino)pyridin-3- yl)methyl)-2-(thiophen-3-yl)acetamide 94 (S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 516;hydrocinnamic acid pyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 517.(1-(4-fluorophenyl) ethylamino)pyridin-3- yl)methyl)-3-phenylpropanamide 95 (S)—N-(2-((6-(5-Cyclopropyl- MS: Calcd.: 559;N-methylhippuric 1H-pyrazol-3-ylamino)-5- Found: [M + H]⁺ 560. acidfluoro-2-(1-(4-fluorophenyl) ethylamino)pyridin-3-yl)methylamino)-2-oxoethyl)- N-methylbenzamide 96(S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 623;(methanesulfonylphenethylamino) pyrazol-3-ylamino)-5-fluoro-2- Found:[M + H]⁺ 624. acetic (1-(4-fluorophenyl) acid ethylamino)pyridin-3-yl)methyl)-2-(N-phenethyl-N- methylsulfonamido)acetamide 97(S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 531; 4-pyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 532.(dimethylamino)benzoic (1-(4-fluorophenyl) acid ethylamino)pyridin-3-yl)methyl)-4-(dimethylamino) benzamide 98 (S)—N-((6-(5-Cyclopropyl-1H-¹H NMR (400 MHz, benzenesulfonyl pyrazol-3-ylamino)-5-fluoro-2- CD₃OD) δchloride (1-(4-fluorophenyl) 7.90-7.88 (m, 2H), 7.65-7.55 (m,ethylamino)pyridin-3- 3H), 7.44-7.41 (m, 2H),yl)methyl)benzenesulfonamide 7.03-6.99 (m, 3H), 5.75 (br s, 1H),5.10-5.08 (m, 1H), 3.88 (dd, J = 35.2, 14.2 Hz, 2H), 1.88-1.84 (m, 1H),1.55 (d, J = 6.8 Hz, 3H), 0.95-0.93 (m, 2H), 0.67-0.64 (m, 2H). MS:Calcd.: 524; Found: [M + H]⁺ 525. 99 (S)—N-((6-(5-Cyclopropyl-1H- MS:Calcd.: 452; cyclopropane pyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺453. carboxylic acid (1-(4-fluorophenyl) ethylamino)pyridin-3-yl)methyl) cyclopropanecarboxamide 100 (S)—N-((6-(5-Cyclopropyl-1H- MS:Calcd.: 477; pyrrole-2-carboxylic pyrazol-3-ylamino)-5-fluoro-2- Found:[M + H]⁺ 478. acid (1-(4-fluorophenyl) ethylamino)pyridin-3-yl)methyl)-1H-pyrrole-2- carboxamide 101 N-((6-(5-Cyclopropyl-1H- MS:Calcd.: 482; tetrahydrofuran-3- pyrazol-3-ylamino)-5-fluoro-2- Found:[M + H]⁺ 483. carboxylic acid ((S)-1-(4-fluorophenyl)ethylamino)pyridin-3- yl)methyl)tetrahydrofuran-2- carboxamide 102(S)—N-((6-(5-Cyclopropyl-1H- MS: Calcd.: 478; 2-furoic acidpyrazol-3-ylamino)-5-fluoro-2- Found: [M + H]⁺ 479. (1-(4-fluorophenyl)ethylamino)pyridin-3- yl)methyl)furan-2- carboxamide 103(S)—N-((6-(5-Cyclopropyl-1H- ¹H NMR (400 MHz, cyclopropylsulfonylpyrazol-3-ylamino)-5-fluoro-2- CD₃OD) δ 7.41 (br s, chloride(1-(4-fluorophenyl) 2H), 7.15 (br s, 1H), ethylamino)pyridin-3-7.01-6.97 (m, 2H), yl)methyl) 6.07 & 5.42 (s, 1H), 5.17 &cyclopropanesulfonamide 5.03 (s, 1H), 4.14 (br s, 2H), 2.58 (br s, 1H),1.88-1.84 (m, 1H), 1.52 (d, J = 6.8 Hz, 3H), 1.10-0.92 (m, 6H), 0.66 (brs, 2H). MS: Calcd.: 488; Found: [M + H]⁺ 489.

Example 104(S)-2-Amino-N-((6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-((S-1-(4-fluorophenyl)ethylamino)pyridin-3-yl)methyl)-3-methylbutanamide

A solution of(S)-3-(aminomethyl)-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine(Example 3; 0.10 g, 0.26 mmol), (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (0.06 g, 0.26 mmol), and HBTU (0.10 g, 0.26 mmol)in DCM (3 ml) was stirred at room temperature for 1 hour. The reactionwas then quenched with a saturated aqueous solution of NaHCO₃, andextracted with DCM (2×50 ml). The combined organic fractions were driedover Na₂SO₄, filtered, and then concentrated. The resulting oil was thenpassed through a silica plug. The resulting foam was placed in dioxane(4 ml) and 4 M HCl in dioxane (1 ml) was then added, and the reactionwas stirred for 3 hours. The reaction was then concentrated to give asolid which was dissolved in a minimal amount of MeOH (0.5 ml) withstirring, followed by fast addition of ether (50 ml). The resultingsolid was filtered, washed with ether, and dried to give the titlecompound (0.033 g, 26%). ¹H NMR (400 MHz, CD₃OD) δ 7.58 (d, J=10.7 Hz,1H), 7.49-7.46 (m, 2H), 7.07-7.02 (m, 2H), 5.80 (s, 1H), 5.09-5.04 (m,1H), 4.58 (dd, J=15.4, 6.8 Hz, 1H), 4.26 (dd, J=15.4, 5.2 Hz, 1H), 3.71(d, J=6.0 Hz, 1H), 2.23-2.18 (m, 1H), 2.01-1.97 (m, 1H), 1.63 (d, J=6.8Hz, 3H), 1.19-1.13 (m, 2H), 1.05-1.03 (m, 6H), 0.85-0.81 (m, 2H). MS:Calcd.: 483. Found: [M+H]⁺ 484.

Example 105(S,E)-N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-5-((cyclopropylimino)methyl)-3-fluoro-N⁶-(1-(4-fluorophenyl)ethylpyridine-2,6-diamine

To a solution of(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde(Example 73, 0.10 g, 0.26 mmol) in THF (5 ml) was added cyclopropanamine(0.03 g, 0.52 mmol) and NaBH(OAc)₃ (0.55 g, 0.26 mmol). The reaction wasstirred for 3 hours, quenched with aqueous Na₂CO₃ (10 ml), and extractedwith DCM (2×20 ml). The combined organic fractions were dried overNa₂SO₄, filtered, and then concentrated. The resulting oil was purifiedby reverse phase column chromatography (5-35% ACN) to give the titlecompound (0.068 g, 62%). ¹H NMR (400 MHz) δ 11.92 (s, 1H), 9.62 (s, 1H),8.93 (s, 1H), 8.35 (s, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.31-7.27 (m, 2H),7.16-7.11 (m, 2H), 6.10 (s, 1H), 5.13-5.10 (m, 1H), 2.96-2.94 (m, 1H),1.89-1.80 (m, 1H), 1.42 (d, J=6.9 Hz, 3H), 0.98-0.88 (m, 2H), 0.76-0.63(m, 2H). MS: Calcd.: 422. Found: [M+H]⁺ 423.

Example 106(S)—N²-(5-Cyclopropyl-1H-pyrazol-3-YD-3-fluoro-N⁶-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine

A mixture ofN-(5-cyclopropyl-1H-pyrazol-3-yl)-3,6-difluoropyridin-2-amine (Method31, 0.10 g, 0.42 mmol) and (S)-1-(4-fluorophenyl)ethanamine (0.3 g, 2.2mmol) were heated to 185° C. under microwave conditions (30 min×3cycles). The resulting dark oil was purified by column chromatography(DCM-MeOH=80:1) to give the title compound (0.04 g, 26%). ¹H NMR (400MHz, CD₃OD) δ 7.08-6.99 (m, 3H), 6.67-6.62 (m, 2H), 6.22 (dd, J=8.9, 2.3Hz, 1H), 5.04 (s, 1H), 4.64-4.59 (m, 1H), 1.16-1.12 (m, 4H), 0.30-0.14(m, 3H), 0.04-0.02 (m, 1H). MS: Calcd.: 355. Found: [M+H]⁺ 356.

Example 107(S)—N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-3-fluoro-N-(1-(4-fluorophenyl)ethyl)-5-((methylamino)methylpyridine-2,6-diamine

To a solution of(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde(Example 73, 0.10 g, 0.26 mmol) in THF (5 ml) was added methylamine (2.0M in THF, 0.52 mmol) and NaBH(OAc)₃ (0.82 g, 0.39 mmol). The reactionwas stirred for 3 hours, quenched with water, and extracted with DCM(2×20 ml). The combined organic fractions were dried over Na₂SO₄,filtered, and then concentrated. The resulting crude imine was dissolvedin MeOH (5 ml) and NaBH₄ (0.06 g, 0.4 mmol) was added. The reaction wasstirred for 10 min, quenched with aq. Na₂CO₃ (10 ml), and extracted withDCM (2×20 ml). The combined organic fractions were dried over Na₂SO₄,filtered, and then concentrated. The resulting oil was purified byreverse phase column chromatography (5-35% ACN) to give the titlecompound (0.05 g, 48%). ¹H NMR (400 MHz, CD₃OD) δ 7.41-7.38 (m, 2H),7.10 (d, J=9.2 Hz, 1H), 7.02-6.98 (m, 2H), 6.00-5.52 (br s, 1H), 5.05(s, 1H), 3.63 (s, 2H), 2.37 (s, 3H), 1.87-1.82 (m, 1H), 1.51 (d, J=6.9Hz, 3H), 0.93-0.91 (m, 2H), 0.67-0.63 (m, 2H). MS: Calcd.: 398. Found:[M+H]⁺ 399.

Example 108(R)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile

A solution of 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoronicotinonitrile (Method 1, 0.3 g, 1.0 mmol) and(R)-1-(4-fluorophenyl)ethanamine (0.3 g, 2.1 mmol) was added to n-BuOH(2 ml) and DIEA (0.18 g, 1.4 mmol) in a sealed tube. The reaction washeated to 140° C. for 48 hours, then cooled to room temperature andconcentrated. The resulting residue was purified by columnchromatography (DCM-MeOH=80:1) to give the title compound (0.11 g, 26%).¹H NMR (400 MHz, CDCl₃) δ 8.44 (br s, 1H), 7.37-7.33 (m, 2H), 7.27 (d,J=9.6 Hz, 1H), 7.07-7.03 (m, 2H), 6.11 (s, 1H), 5.24-5.20 (m, 2H),1.87-1.83 (m, 1H), 1.60 (d, J=6.2 Hz, 3H), 1.01-0.98 (m, 2H), 0.79-0.65(m, 2H). MS: Calcd.: 380. Found: [M+H]⁺ 381.

Example 109(S)—N-((6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)pyridin-3-yl)methyl)-1,1,1-trifluoromethanesulfonamide

To a solution of(S)-3-(aminomethyl)-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine(Example 3, 0.10 g, 0.26 mmol) in THF (5 ml) at room temperature wasadded 1.1 equivalent of trifluoromethylsulfonyl chloride loaded TFPresin, and DMAP (0.031 g, 0.26 mmol). The reaction was then stirred atroom temperature for 15 hours and filtered. The remaining resin was thenwashed with THF (2×10 ml for 20 min), and then combined organicfractions were concentrated. The resulting oil was purified byreverse-phase column chromatography (5-50% ACN) to give the titlecompound (0.02 g, 15%). ¹H NMR (400 MHz, CD₃OD) δ7.40-7.37 (m, 2H), 7.17(d, J=10.9 Hz, 1H), 7.02-6.97 (m, 2H), 5.90-5.60 (br s, 1H), 5.14-5.12(m, 1H), 4.28-4.25 (m, 2H), 1.88-1.84 (m, 1H), 1.54 (d, J=7.0 Hz, 3H),0.95-0.93 (m, 2H), 0.67-0.64 (m, 2H). MS: Calcd.: 516. Found: [M+H]⁺517.

Example 110(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(5-fluoropyridin-2-yl)ethylamino)nicotinonitrile

A suspension of6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,5-difluoronicotinonitrile(Method 32, 5.75 g, 22.0 mmol), in n-BuOH (28.75 ml) was prepared atroom temperature in a 48 ml sealed tube. DIEA (4.98 ml, 28.6 mmol) wasthen added, followed by the addition of(S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 33; 4.0 g, 28.6 mmol).The tube was then sealed, and the suspension was heated to 130° C. over45 minutes. The reaction was then allowed to stir at 130° C. for 18hours. The reaction was then cooled to room temperature and concentratedby rotary evaporation at 60° C. to remove n-BuOH. The remaining oil wasthen taken up in DCM (100 ml) and washed with water (2×100 ml). Thecombined aqueous fractions were then extracted with DCM (100 ml), andthe combined organic fractions were dried over Na₂SO₄, filtered andconcentrated. The resulting oil was then purified by columnchromatography (DCM, then DCM-MeOH=100:1) to give the title compound(5.2 g, 62%). ¹H NMR (400 MHz, CD₃OD) δ 8.43 (d, J=2.5 Hz, 1H),7.60-7.34 (m, 3H), 6.09-5.63 (m, 1H), 5.24 (q, J=7.0 Hz, 1H), 1.91(septet, 1H), 1.58 (d, J=6.6 Hz, 3H), 1.08-0.90 (m, 2H), 0.79-0.70 (m,2H). MS: Calcd.: 381. Found: [M+H]⁺ 382.

Example 111(S)—N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-3-fluoro-N⁶-(1-(4-fluorophenyl)ethyl)-5-isopropylpyridine-2,6-diamine

To a solution of(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde(Example 73, 0.15 g, 0.39 mmol) in THF (6 ml) at 0° C. was added methylmagnesiumbromide (1.4 M THF, 0.50 mmol). The reaction was then stirredfor 4 hours at room temperature, quenched with water, and extracted withDCM (2×20 ml). The combined organic fractions were dried over Na₂SO₄,filtered, and then concentrated. The resulting oil was purified byreverse phase column chromatography (5-50% ACN) to give the titlecompound (0.10 g, 64%). ¹H NMR (400 MHz, CD₃OD) δ 7.40-7.37 (m, 2H),7.12 (d, J=11.9 Hz, 1H), 7.02-6.97 (m, 2H), 5.70 (s, 1H), 5.17-5.12 (m,1H), 2.99-2.96 (m, 1H), 1.87-1.82 (m, 1H), 1.54 (d, J=7.0 Hz, 3H),1.23-1.21 (m, 6H), 0.94-0.90 (m, 2H), 0.66-0.63 (m, 2H). MS: Calcd.:397. Found: [M+H]⁺ 398.

Example 112(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-(isopropylamino)nicotinonitrile

To a solution of(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-iodonicotinonitrile(Example 134, 0.07 g, 0.14 mmol) and DIEA (0.023 g, 0.18 mol) in n-BuOH(1.5 ml) was added isopropylamine (0.16 g, 2.7 mmol). The reaction wasthen heated to 185° C. under microwave conditions (1 hour×4 cycles). Thereaction was then cooled to room temperature, DCM (10 ml) was added, andwashed with 10% aqueous Na₂S₂O₃. The organic layer was then dried overNa₂SO₄, filtered, and then concentrated. The resulting oil was purifiedby reverse-phase column chromatography (5-50% ACN) to give the titlecompound (0.031 g, 51%). ¹H NMR (400 MHz, CD₃OD) δ 7.36-7.33 (m, 2H),7.04-7.00 (m, 2H), 5.99-5.59 (br s, 1H), 5.14 (s, 1H), 4.29-4.23 (m,1H), 1.87-1.83 (m, 1H), 1.52 (d, J=7.0 Hz, 3H), 1.25 (d, J=6.2 Hz, 6H),0.95-0.94 (m, 2H), 0.65-0.63 (m, 2H). MS: Calcd.: 437. Found: [M+H]⁺438.

Example 113(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-(methylamino)nicotinonitrile

To a solution of(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-iodonicotinonitrile(Example 134, 0.10 g, 0.19 mmol) and DIEA (0.03 g, 0.25 mol) in n-BuOH(1.5 ml) was added methylamine (2.0 M in THF, 1.9 mmol). The reactionwas then heated to 185° C. under microwave conditions (1 hour×2 cycles).The reaction was then cooled to room temperature, DCM (10 ml) was added,and washed with 10% aqueous Na₂S₂O₃. The organic layer was then driedover Na₂SO₄, filtered, and then concentrated. The resulting oil waspurified by reverse-phase column chromatography (5-50% ACN) to give thetitle compound (0.04 g, 49%). ¹H NMR (400 MHz, CD₃OD) δ 7.35 (br s, 2H),7.04-7.00 (m, 2H), 5.95 (br s, 1H), 5.14 (br s, 1H), 3.15 (d, J=2.7 Hz,3H), 1.87-1.82 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 0.95-0.94 (m, 2H),0.65-0.63 (m, 2H). MS: Calcd.: 409; Found: [M+H]⁺ 410.

Example 114(S)-5-Fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)nicotinonitrile

A suspension of2,5-difluoro-6-(5-methyl-1H-pyrazol-3-ylamino)nicotinonitrile (Method41, 0.20 g, 0.85 mmol), DIEA (0.14 g, 1.1 mmol), and(S)-1-(4-fluorophenyl)ethanamine (0.23 g, 1.7 mmol) in n-BuOH (2 ml) washeated to 130° C. for 18 hours. The reaction was then cooled to roomtemperature, diluted with water (20 ml), and extracted with DCM (2×50ml). The combined organic fractions were dried over Na₂SO₄, filtered,and then concentrated. The resulting oil was purified by columnchromatography (DCM-MeOH=100:1) to give the title compound (0.27 g,91%). ¹H NMR (400 MHz, CD₃OD) δ 7.38-7.32 (m, 3H), 7.03-6.99 (m, 2H),5.99 (br s, 1H), 5.15-5.14 (m, 1H), 2.24 (s, 3H), 1.53 (d, J=6.8 Hz,3H). MS: Calcd.: 354. Found: [M+H]⁺ 355.

Example 115(S)-5-Fluoro-2-(1-(5-fluoropyridin-2-yl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)nicotinonitrile

A suspension of2,5-difluoro-6-(5-methyl-1H-pyrazol-3-ylamino)nicotinonitrile (Method41, 0.24 g, 1.02 mmol), DIEA (0.17 g, 1.3 mmol), and(S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 33, 0.21 g, 1.5 mmol) inn-BuOH (2 ml) was heated to 130° C. for 18 hours. The reaction wascooled to room temperature, diluted with water (20 ml), and extractedwith DCM (2×50 ml). The combined organic fractions were dried overNa₂SO₄, filtered, and then concentrated. The resulting oil was purifiedby column chromatography (DCM-MeOH 100:1) to give the title compound(0.20 g, 55%). ¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 7.51-7.38 (m,3H), 6.01 (s, 1H), 5.21-5.19 (m, 1H), 2.27 (s, 3H), 1.58 (d, J=6.7 Hz,3H). MS: Calcd.: 355. Found: [M+H]⁺ 356.

Example 116(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(5-fluoropyridin-2-yl)ethylamino)nicotinamide

A solution of(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(5-fluoropyridin-2-yl)ethylamino)nicotinonitrile(Example 110, 0.24 g, 0.62 mmol) in MeOH (20 ml) was prepared at roomtemperature. An aqueous solution (0.7 ml) of KOH (0.17 g, 3.15 mmol) wasthen added dropwise, followed by the addition of 0.05 ml of 30% H₂O₂.The reaction was then heated to 65° C. for 3 hours, cooled to roomtemperature, and concentrated. The resulting residue was dissolved inEtOAc (50 ml), and washed with water (50 ml). The organic fraction wasthen dried over Na₂SO₄, filtered, and then concentrated. The resultingoil was purified by column chromatography (DCM-MeOH=30:1) to give thetitle compound (0.13 g, 52%). ¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H),7.70 (d, J=12.1 Hz, 1H), 7.48-7.38 (m, 2H), 6.02 (s, 1H), 5.25-5.02 (m,1H), 1.91-1.86 (m, 1H), 1.57 (d, J=7.0 Hz, 3H), 0.97 (br s, 2H), 0.73(br s, 2H). MS: Calcd.: 399. Found: [M+H]⁺ 400.

Example 117(S)—N-((6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-((S)-1-(4-fluorophenyl)ethylamino)pyridin-3-yl)methyl)-5-oxopyrrolidine-2-carboxamide

To a DCM (10 ml) solution of(S)-3-(aminomethyl)-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine(Example 3, 0.45 g, 1.17 mmol) and HBTU (0.44 g, 1.17 mmol) cooled at 0°C. was added a solution of (S)-5-oxopyrrolidine-2-carboxylic acid (0.15g, 1.17 mmol) in DMF (5 ml), followed by the addition of DIEA (0.14 g,1.17 mmol). The reaction was then stirred at room temperature for 1 hourand quenched with 20 ml of aqueous NaHCO₃, and extracted with DCM (2×30ml). The combined organic fractions were dried over Na₂SO₄, filtered,and then concentrated. The resulting oil was purified by columnchromatography (DCM-MeOH=20:1) to give the title compound (0.30 g, 51%).¹H NMR (400 MHz, CD₃OD) δ 7.35-7.32 (m, 2H), 7.10 (d, J=10.9 Hz, 1H),7.00-6.96 (m, 2H), 5.80-5.65 (br s, 1H), 5.06-5.05 (m, 1H), 4.30-4.15(m, 3H), 2.45-2.24 (m, 3H), 2.05-2.00 (m, 1H), 1.85-1.80 (m, 1H), 1.48(d, J=6.8 Hz, 3H), 0.91-0.89 (m, 2H), 0.63-0.62 (m, 2H). MS: Calcd.:495. Found: [M+H]⁺ 496.

Example 118(R)—N-((6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-((S)-1-(4-fluorophenyl)ethylamino)pyridin-3-yl)methyl)-5-oxopyrrolidine-2-carboxamide

To a DCM (10 ml) solution of(S)-3-(aminomethyl)-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine(Example 3; 0.45 g, 1.17 mmol) and HBTU (0.44 g, 1.17 mmol) cooled at 0°C. was added a solution of (R)-5-oxopyrrolidine-2-carboxylic acid (0.15g, 1.17 mmol) in DMF (5 ml), followed by the addition of DIEA (0.14 g,1.17 mmol). The reaction was then stirred at room temperature for 1 hourand quenched with 20 ml aqueous NaHCO₃, and extracted with DCM (2×30ml). The combined organic fractions were dried over Na₂SO₄, filtered,and then concentrated. The resulting oil was purified by columnchromatography (DCM-MeOH=20:1) to give the title compound (0.25 g, 43%).¹H NMR (400 MHz, CD₃OD) δ 7.37-7.34 (m, 2H), 7.14 (d, J=10.9 Hz, 1H),7.02-6.97 (m, 2H), 5.80-5.65 (br s, 1H), 5.07 (br s, 1H), 4.33-4.16 (m,3H), 2.46-2.22 (m, 3H), 2.05-1.98 (m, 1H), 1.88-1.81 (m, 1H), 1.51 (d,J=6.8 Hz, 3H), 0.93-0.92 (m, 2H), 0.66-0.62 (m, 2H). MS: Calcd.: 495.Found: [M+H]⁺ 496.

Example 119(S)-5-Fluoro-2-(1-(5-fluoropyridin-2-yl)ethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile

A solution of2,5-difluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile(Method 42, 0.30 g, 1.07 mmol), DIEA (0.16 g, 1.29 mmol), and(S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 33; 0.22 g, 1.6 mmol) inn-BuOH (3 ml) was heated to 130° C. for 18 hours. The reaction was thencooled to room temperature, diluted with water (20 ml), and extractedwith DCM (2×50 ml). The combined organic fractions were dried overNa₂SO₄, filtered, and then concentrated. The resulting oil was purifiedby column chromatography (hexanes-EtOAc=3:1) to give the title compound(0.25 g, 58%). ¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.56-7.55 (m,2H), 7.45 (d, J=10.5 Hz, 1H), 5.42 (s, 1H), 5.25-5.22 (m, 1H), 4.63 (brs, 1H), 1.60 (d, J=7.0 Hz, 3H), 1.34 (d, J=6.1 Hz, 6H). MS: Calcd.: 399.Found: [M+H]⁺ 400.

Example 1206-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]-2-{[(1S)-1-(3,5-difluoropyridin-2-yl)ethyl]amino}-5-fluoronicotinonitrile

Following a similar procedure to the synthesis of Example 1, the titlecompound was synthesized from6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2,5-difluoronicotinonitrile(Method 32) and (S)-1-(3,5-difluoropyridin-2-yl)ethanamine (Method 50).¹H NMR (400 MHz) δ 0.68 (m, 2H), 0.95 (m, 2H), 1.45 (d, J=6 Hz, 3H),1.87 (m, 1H), 5.48 (m, 1H), 6.19 (s, 1H), 6.69 (m, 1H), 7.63 (d, 1H),7.98 (m, 1H), 8.51 (s, 1H), 9.58 (s, 1H), 12.15 (s, 1H). MS: Calcd.:399. Found: [M+H]⁺ 400.

Example 121(S)-5-Chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-(1-(5-fluoropyrimidin-2-yl)ethylamino)nicotinonitrile

A mixture of2,5-dichloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)nicotinonitrile(Method 43, 0.17 g, 0.58 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamineHCl salt (Method 55, 0.186 g, 0.87 mmol), and DIEA (0.60 ml, 3.5 mmol)in n-BuOH (3 ml) was heated in a sealed tube at 130° C. for 44 hours.The solvent was removed under reduced pressure and the residue waspurified by column chromatography (hexane-EtOAc=1:1) to give the titlecompound as a white solid (0.095 g, 41%). ¹H NMR (400 MHz) δ 12.16 (s,1H), 8.88 (s, 2H), 8.52 (s, 1H), 7.84 (s, 1H), 7.05 (d, J=7.2 Hz, 1H),5.98 (s, 1H), 5.28 (m, 1H), 1.84 (m, 1H), 1.57 (d, J=7.2 Hz, 3H), 0.96(m, 2H), 0.71 (m, 2H). MS: Calcd.: 398. Found: [M+H]⁺ 399.

Example 122N-{5-[(1R)-1-({3-Cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamideand Example 123N-{5-[(1S)-1-({3-Cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamide

To a 10-ml microwave vessel was added,2-chloro-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoronicotinonitrile(Method 1, 600 mg, 2.3 mmol),N-[5-(1-aminoethyl)-2-fluorophenyl]methanesulfonamide (Method 61, 500mg, 2.3 mmol), DIEA (0.5 ml, 2.76 mmol), and n-butanol (5 ml). Thevessel was sealed and subjected to microwave heating at 150° C. for 5hours (CEM Discover System). The resulting mixture was then purified bysilica gel chromatography using 5% MeOH/DCM. The racemic productobtained was then chirally purified by HPLC on Chiralcel OJ column(500×50 mm, 20 microns) using 50:25:25:0.1% ofhexane/MeOH/EtOH/diethylamine at 118 ml/min. The chiral purificationgave 220 mg ofN-{5-[(1R)-1-({3-cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamide¹H NMR: δ 11.77-12.26 (br s, 1H), 9.51 (s, 1H), 9.34-9.48 (br s, 1H),7.62 (d, J=10.55 Hz, 1H), 7.39 (d, J=8.29 Hz, 1H), 7.02-7.23 (m, 3H),6.00 (s, 1H), 5.07-5.24 (m, 1H), 2.95 (s, 3H), 1.81-1.95 (m, 1H), 1.49(d, J=7.54 Hz, 3H), 0.88-0.97 (m, 2H), 0.57-0.68 (m, 2H). MS: Calcd.:473. Found: [M+H]⁺ 474 and 223 mg ofN-{5-[(1S)-1-({3-cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamidel;¹H NMR: 11.73-12.38 (br s, 1H), 9.42 (s, 1H), 8.41-9.12 (br s, 1H), 7.61(d, J=11.30 Hz, 1H), 7.37 (d, J=7.54 Hz, 1H), 6.96-7.24 (m, 3H), 6.02(s, 1H), 5.05-5.26 (m, 1H), 2.90 (s, 3H), 1.79-1.96 (m, 1H), 1.49 (d,J=6.78 Hz, 3H), 0.89-0.98 (m, 2H), 0.59-0.67 (m, 2H). MS: Calcd.: 473.Found: [M+H]⁺ 474.

Example 1245-Chloro-2-{[(1S)-1-(5-fluoropyridin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]nicotinonitrile

To a 10-ml microwave vessel was added,2,5-dichloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]nicotinonitrile (Method60, 8 mmol), [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine (Method 33, 8mmol, 97 wt % solution in dioxane), DIEA (0.3 ml, 1.66 mmol), andn-butanol (4 ml). The vessel was then sealed and subjected to microwaveheating at 150° C. for 3 hours. After 3 hours, more 2-pyridyl amine (100mg, 0.69 mmol) was added. The resulting mixture was purified by silicagel chromatography (Biotage Horizon System) using an isocratic system of15:0.5:0.5% of DCM/EtOAc/MeOH to give 312 mg of the title compound. ¹HNMR: 12.04 (br s, 1H), 8.41-8.63 (m, 2H), 7.84 (s, 1H), 7.56-7.71 (m,1H), 7.40 (dd, J=8.67, 4.14 Hz, 1H), 7.28 (s, 1H), 5.86 (s, 1H),5.06-5.25 (m, 1H), 2.17 (s, 3H), 1.51 (d, J=7.54 Hz, 3H). MS: Calcd.:371/373. Found: [M+H]⁺ 372/374.

Example 125N-{5-[1-({3-Cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}acetamide

To a 10-ml microwave reaction vessel was added,6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2,5-difluoronicotinonitrile(Method 32, 300 mg, 1.13 mmol), N-[5-(1-aminoethyl)-2-fluorophenyl]acetamide (Method 66, 331 mg, 1.7 mmol), and DIEA (0.8ml, 4.6 mmol) in n-butanol (4 ml). The resulting suspension was set tomicrowave heating (CEM Discover System) at 150° C. for 3 hours. Thereaction was concentrated in vacuo and purified by silica gelchromatography (Biotage Horizon System) using a gradient elution of25-35% EtOAc (20% v/v MeOH) in hexanes to give 180 mg (36% isolatedyield) of the title compound. ¹H NMR: 9.66 (br s, 1H) 9.43 (s, 1H) 7.81(d, J=6.03 Hz, 2H) 7.60 (d, J=11.30 Hz, 1H) 6.92-7.21 (m, 3H) 5.98 (s,1H) 5.13 (t, J=7.16 Hz, 1H) 2.05 (s, 3H) 1.76-1.92 (m, 1H) 1.46 (d,J=6.78 Hz, 3H) 0.82-0.95 (m, J=8.29 Hz, 2H) 0.54-0.66 (m, 2H). MS:Calcd.: 437. Found: [M+H]⁺ 438.

Example 126N-{5-[1-({3-Cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}cyclopropanecarboxamide

To a 10-ml microwave reaction vessel was added6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2,5-difluoronicotinonitrile(Method 32, 431 mg, 1.65 mmol), N-[5-(1-aminoethyl)-2-fluorophenyl]cyclopropanecarboxamide (Method 69, 550 mg, 2.5 mmol),and DIEA (1.15 ml, 6.6 mmol) in n-butanol (5 ml). The resultingsuspension was set to microwave heating (CEM Discover System) at 150° C.for 3 hours. The reaction was concentrated in vacuo and purified bysilica gel chromatography (Biotage Horizon System) using a gradientelution of 25-35% EtOAc (20% v/v MeOH) in hexanes to give 267 mg (35%isolated yield) of the title compound. ¹H NMR: 11.99 (s, 1H) 9.91 (s,1H) 9.42 (s, 1H) 7.88 (d, J=6.03 Hz, 1H) 7.59 (d, J=10.55 Hz, 1H)6.95-7.20 (m, 3H) 5.99 (s, 1H) 5.02-5.21 (m, 1H) 1.89-2.03 (m, 1H)1.76-1.89 (m, 1H) 1.45 (d, J=7.54 Hz, 3H) 0.87 (t, J=8.67 Hz, 2H) 0.75(d, J=6.03 Hz, 4H) 0.54-0.66 (m, 2H). MS: Calcd.: 463. Found: [M+H]⁺464.

Example 1276-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoro-2-{[(1S)-1-(6-fluoropyridin-3-yl)ethyl]amino}nicotinonitrileand Example 1286-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoro-2-{[(1R)-1-(6-fluoropyridin-3-yl)ethyl]amino}nicotinonitrile

To a 10-ml microwave reaction vessel was added6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2,5-difluoronicotinonitrile(Method 32, 1 g, 4 mmol), 1-(6-fluoropyridin-3-yl)ethanamine (Method 76,560 mg, 4 mmol), and DIEA (0.84, 4.8 mmol) in n-butanol (5 ml). Theresulting suspension was set to microwave heating (CEM Discover System)at 150° C. for 3 hours. The reaction was then concentrated in vacuo andpurified by silica gel chromatography (Biotage Horizon System) using agradient elution of 1-4% MeOH in DCM to give 380 mg (25% isolated yield)of6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoro-2-{[1-(6-fluoropyridin-3-yl)ethyl]amino}nicotinonitrile.The racemic product obtained was then chirally purified by HPLC onChiralpak AS column (500×50 mm, 20 microns) using 80:10:10:0.1% ofhexane-MeOH-EtOH-diethylamine at 118 ml/min. The chiral purificationgave 145 mg of6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoro-2-{[(1S)-1-(6-fluoropyridin-3-yl)ethyl]amino}nicotinonitrile:¹H NMR: 9.43 (s, 1H) 8.08 (s, 1H) 7.84-8.00 (m, 1H) 7.61 (d, J=11.30 Hz,1H) 7.18 (d, J=7.54 Hz, 1H) 7.04-7.13 (m, 1H) 5.94 (s, 1H) 5.15 (t,J=7.54 Hz, 1H) 1.81-1.97 (m, 1H) 1.51 (d, J=7.54 Hz, 3H) 0.92 (d, J=6.03Hz, 2H) 0.64 (s, 2H). MS: Calcd.: 381. Found: [M+H]⁺ 382; and 137 mg of6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoro-2-{[(1R)-1-(6-fluoropyridin-3-yl)ethyl]amino}nicotinonitrile:¹H NMR: 9.42 (s, 1H) 8.08 (s, 1H) 7.93 (t, J=8.29 Hz, 1H) 7.61 (d,J=10.55 Hz, 1H) 7.18 (d, J=8.29 Hz, 1H) 7.08 (dd, J=8.29, 3.01 Hz, 1H)5.94 (s, 1H) 5.15 (t, J=7.54 Hz, 1H) 1.81-1.96 (m, 1H) 1.51 (d, J=7.54Hz, 3H) 0.91 (d, J=8.29 Hz, 2H) 0.64 (s, 2H). MS: Calcd.: 381. Found:[M+H]⁺ 382.

Example 1295-Fluoro-2-{[1-(5-fluoropyrimidin-2-ylethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]nicotinonitrile

A mixture of 1-(5-fluoropyrimidin-2-yl)ethanamine (Method 72, 0.05 g,0.35 mmol),2,5-difluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]nicotinonitrile (Method41, 0.06 g, 0.25 mmol), and DIEA (0.12 ml, 0.7 mmol) in n-BuOH (3 ml)was charged into a microwave reaction vessel. The vessel was sealed andheated in microwave reactor at 160° C. for 6 hours. The solvent wasremoved under reduced pressure and the residue was purified by silicagel chromatography (DCM-EtOAc=1:1) to give the title compound as ayellow solid (0.016 g, 15%). LC-MS, 357 (M+1). ¹H NMR (400 MHz, MeOD) δ8.70 (s, 2H), 7.45 (d, 1H), 6.40 (br, 1H), 5.45 (q 1H), 2.35 (s, 3H),1.65 (d, 3H).

Example 1305-Chloro-2-{[1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]nicotinonitrile

A mixture of 1-(5-fluoropyrimidin-2-yl)ethanamine (Method 72, 0.05 g,0.35 mmol),2,5-dichloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]nicotinonitrile (Method60, 0.06 g, 0.25 mmol), and DIEA (0.12 ml, 0.7 mmol) in n-BuOH (10 ml)was charged into a microwave reaction vessel. The vessel was sealed andheated in microwave reactor at 160° C. for 6 hours. The solvent wasremoved under reduced pressure and the residue was purified by silicagel chromatography (DCM-EtOAc=1:1) to give the title compound as ayellow solid (0.017 g, 15%). LC-MS, 373 (M+1). ¹H NMR (400 MHz, MeOD) δ8.75 (s, 2H), 7.45 (s, 1H), 6.40 (s, 1H), 5.45 (br 1H), 2.35 (s, 3H),1.60 (d, 3H).

Example 131N-{5-[(1S)-1-({3-Cyano-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamideand Example 132N-{5-[(1R)-1-({3-Cyano-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamide

A mixture of N-[5-(1-aminoethyl)-2-fluorophenyl]methanesulfonamide(Method 61, 0.2 g, 0.86 mmol),2,5-difluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]nicotinonitrile (Method41, 0.2 g, 0.8 mmol), and DIEA (0.3 ml, 2.1 mmol) in n-BuOH (4 ml) wascharged into a microwave reaction vessel. The vessel was sealed andheated in microwave reactor at 160° C. for 6 hours. The solvent wasremoved under reduced pressure and the residue was purified by silicagel chromatography (DCM-EtOAc=1:1) to give the title compound as ayellow solid (0.16 g, 35%). The resulting racemic compound was separatedby a Chiralpak AS-H SFC HPLC column (25% MeOH) to two enantiomers (Theretention time of the first elute Example 131 (S-isomer) was 7 min, andthe retention time of the second elute Example 132 (R-isomer) was 8.5min). LC-MS, 448 (M+1). ¹H NMR (400 MHz, MeOD) δ 7.45 (d, 1H), 7.40 (d,1H), 7.20 (s, 1H), 7.10 (t, 1H), 6.00 (s, 1H), 5.20 (br 1H), 2.90 (s,3H), 2.20 (s, 3H), 1.60 (d, 3H).

Example 1335-Fluoro-2-{[1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-isopropoxy-1H-pyrazol-3-yl)amino]nicotinonitrile

A mixture of 1-(5-fluoropyrimidin-2-yl)ethanamine (Method 72, 0.05 g,0.35 mmol),2,5-difluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]nicotinonitrile (Method41, 0.05 g, 0.25 mmol), and DIEA (0.12 ml, 0.7 mmol) in n-BuOH (4 ml)was charged into a microwave reaction vessel. The vessel was sealed andheated in microwave reactor at 160° C. for 6 hrs. The solvent wasremoved under reduced pressure and the residue was purified by silicagel chromatography (DCM-EtOAc=1:1) to give the title compound as ayellow solid (0.006 g, 5%). LC-MS, 401 (M+1). ¹H NMR (400 MHz, MeOD) δ8.70 (s, 2H), 7.50 (d, 1H), 5.50 (s, 1H), 5.45 (br, 1H), 4.60 (m, 1H),1.60 (d, 3H), 1.25 (d, 6H).

Example 134(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-iodonicotinonitrile

A solution of2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-4-iodonicotinonitrile(Method 39, 0.28 g, 0.69 mmol), (S)-1-(4-fluorophenyl)ethanamine (0.19g, 1.3 mmol), and DIEA (0.11 g, 0.90 mmol) in n-BuOH (1 ml) was heatedto 140° C. for 18 hours. The reaction was diluted with water (10 ml),extracted with DCM (2×20 ml) and the combined organic fractions weredried over Na₂SO₄, filtered, and then concentrated. The resulting oilwas purified by column chromatography (DCM-MeOH=100:1) to give the titlecompound (0.07 g, 20%). MS: Calcd.: 506. Found: [M+H]⁺ 507.

Preparation of Starting Materials

Method 1

2-Chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoronicotinonitrile

A solution of 5-cyclopropyl-1H-pyrazol-3-amine (1.9 g, 16.0 mmol) inCH₃CN (20 ml) was added dropwise to a solution of2,6-dichloro-5-fluoronicotinonitrile (3.0 g, 16.0 mmol) andtriethylamine (2.1 g, 20.0 mmol) in CH₃CN (80 ml) at 25° C. Theresulting solution was then heated to 82° C. for 18 hrs, and then cooledto 25° C., at which point the product precipitated from solution. Theresulting solid was filtered, and washed with CH₃CN (100 ml) to give thetitle compound (3.2 g, 73%). MS: Calcd.: 277. Found: [M+H]⁺ 278.

Method 2

2-Chloro-5-fluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile

A solution of 5-isopropoxy-1H-pyrazol-3-amine (0.96 g, 6.8 mmol),2,6-dichloro-5-fluoronicotinonitrile (1.3 g, 6.8 mmol), andtriethylamine (0.9 g, 8.8 mmol) in THF (30 ml) was heated to 60° C. for4 days, and then cooled to 25° C., at which point the productprecipitated. The resulting solid was filtered and washed with hexanes(100 ml) to give the title compound (1.0 g, 50%). MS: Calcd.: 295.Found: [M+H]⁺ 296.

Method 3

3,5,6-Trichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyridin-2-amine

A solution of 2,3,5,6-tetrachloropyridine (0.20 g, 0.9 mmol),5-cyclopropyl-1H-pyrazol -3-amine (0.20 g, 1.8 mmol), and triethylamine(0.10 g, 1.4 mmol) in NMP (2 ml) was heated in a microwave at 200° C.for 30 min. The reaction was cooled to 25° C., quenched with water (10ml), and extracted with MTBE (4×30 ml). The combined organic fractionswere then dried, filtered, and concentrated. The resulting solid waspurified by column chromatography (DCM-MeOH=50:1) to give the titlecompound (0.035 g, 12%). MS: Calcd.: 303. Found: [M+H]⁺ 303.

Method 4

(2-Chloro-pyridin-4-yl)-(5-cyclopropyl-1H-pyrazole-3-yl)-amine

A mixture of 4-iodo-2-chloropyridine (0.26 g, 1.1 mmol),3-amino-5-cyclopropyl-pyrazole -1-carboxylic acid tert-butyl ester (0.20g, 0.89 mmol), Pd₂dba₃ (0.016 g, 2 mol %), Xantphos (0.031 g, 6 mol %),and Cs₂CO₃ (0.41 g, 1.3 mmol) in degassed toluene (4 ml) was purged withN₂ and heated to 100° C. in a sealed tube for 2 days. The mixture wasdiluted with THF and filtered to remove Cs₂CO₃. The filtrate wasconcentrated under reduced pressure and purified by columnchromatography (hexane-EtOAc=3:1) to give the title compound (0.10 g,48%). MS: Calcd.: 234. Found: [M+H]⁺ 235.

Method 5

(S)-6-Chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine

To a mixture of 2,6-dichloro-3-nitropyridine (2.26 g, 10.8 mmol) andpotassium carbonate (1.29 g, 9.34 mmol) in anhydrous CH₃CN (20 ml), wasadded (S)-1-(4-fluoro-phenyl)-ethylamine (1.00 g, 7.19 mmol) dropwise at0° C. The reaction mixture was stirred at 25° C. for 17 hrs. The solidwas removed by filtration and the resulted cake was washed with EtOAc(20 ml). The combined filtrate was concentrated and purified by columnchromatography (hexane-EtOAc=10:1) to give the title compound as ayellow solid (1.74 g, 82%). ¹H NMR (400 MHz) δ 8.65 (d, J=7.6 Hz, 1H),8.43 (d, J=8.4 Hz, 1H), 7.51 (m, 2H), 7.16 (m, 2H), 6.81 (d, J=8.8 Hz,1H), 5.37 (m, 1H), 1.59 (d, J=6.8 Hz, 3H).

Methods 6-9

Following a similar procedure to Method 5, the following compounds weresynthesized from a 2,6-dichloro-3-nitropyridine by reacting it with anamine.

Method Product NMR/MS Amine 6 6-Chloro-N-(4- (400 MHz, CDCl₃) 8.58 (brs, 1H), (4-fluoro-phenyl) fluorobenzyl)-3- 8.37 (d, J = 8.4 Hz, 1H),7.36 (m, 2H), methanamine nitropyridin-2-amine 7.04 (m, 2H), 6.67 (d, J= 8.4 Hz, 1H), 4.78 (d, J = 5.6 Hz, 2H) 7 (2R)-2-[(6-Chloro-3- (400 MHz)8.96 (d, J = 7.6 Hz, 1H), (R)-2-amino-2-(4- nitropyridin-2- 8.46 (d, J =8.4 Hz, 1H), 7.45 (m, 2H), fluorophenyl) yl)amino]-2-(4- 7.15 (m, 2H),6.81 (d, J = 8.8 Hz, 1H), ethanol fluorophenyl)ethanol 5.27 (m, 2H),3.80 (m, 2H) 8 2-[(6-Chloro-3- (400 MHz) 9.13 (s, 1H), 8.44 (d, J = 8.4Hz, Method 10 nitropyridin-2- 1H), 7.39 (m, 2H), 7.06 (m,yl)amino]-2-(4- 2H), 6.73 (d, J = 8.8 Hz, 1H), 5.16 (t,fluorophenyl)propane- J = 5.6 Hz, 2H), 4.07 (m 2H), 3.96 (m, 1,3-diol2H). MS: Calcd.: 341; Found: [M + H]⁺ 342 9 6-Chloro-N-[(1R)-1- MS:Calcd.: 295; Found: [M + H]⁺ 296 (R)-1-(4-fluoro (4-fluorophenyl)phenyl) ethyl]-3-nitropyridin- ethanamine 2-amineMethod 10

2-Amino-2-(4-fluorophenyl)propane-1,3-diol

A suspension of 2-(4-fluorophenyl)-2-nitroproane-1,3-diol (Method 11;4.5 g, 20.9 mmol) and Raney nickel (0.45 g, 5.23 mmol) in MeOH (50 ml)was degassed and stirred under H₂ (48 psi) for 2 hours. The catalyst wasremoved by filtration. The filtrate was concentrated and recrystallizedfrom hexane:EtOAc (1:1) to give the title compound (2.35 g, 61%) as awhite solid. NMR (400 MHz) 7.55 (m, 2H), 7.07 (m, 2H), 4.65 (t, J=5.2Hz, 2H), 3.49 (m, 4H), 1.76 (s, 2H).

Method 11

2-(4-Fluorophenyl)-2-nitroproane-1,3-diol

To a solution of 1-fluoro-4-(nitromethyl)benzene (Method 12; 10.0 g, 80%pure; 52 mmol) and TEA (15.1 ml, 108.3 mmol) in dioxane (50 ml) wasadded formaldehyde (8.6 ml, 116 mmol) dropwise at 0° C. After addition,the reaction was slowly warmed up to 25° C. overnight. The solvent wasremoved under reduced pressure and the residue was purified by columnchromatography (hexane:EtOAc=10:1) to give the title compound as a whitesolid (4.5 g, 41%). NMR (400 MHz) 7.41 (m, 2H), 7.22 (m, 2H), 5.39 (t,J=5.2 Hz, 2H), 4.22 (m, 4H).

Method 12

1-Fluoro-4-(nitromethyl)benzene

A mixture of 1-(bromomethyl)-4-fluorobenzene (11.52 g, 61 mmol) andAgNO₂ (11.3 g, 73 mmol) in benzene (200 ml) was stirred vigorously at25° C. for 25 hrs. The solid was removed by filtration and washed withether (500 ml). The combined organic was concentrated to give the titlecompound (10.0 g, 80% pure; 85%) which was used without furtherpurification. NMR (400 MHz, CDCl₃) 7.44 (m, 2H), 7.18 (m, 2H), 5.42 (s,2H).

Method 13

(S)-5,6-Chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine

To a mixture of 2,3,6-trichloro-5-nitropyridine (1.00 g, 4.40 mmol) andpotassium carbonate (0.79 g, 5.7 mmol) in anhydrous acetonitrile (10 ml)was added (S)-1-(4-fluoro-phenyl)-ethylamine (0.64 g, 4.62 mmol)dropwise at 0° C. After addition, the reaction mixture was stirred at25° C. for 17 hours. The solid was removed by filtration and washed withEtOAc (20 ml). After evaporation of the solvent, the resulted residuewas purified by column chromatography (hexane:EtOAc=10:1) to give thetitle compound as a yellow solid (0.61 g, 79% pure, 33%). NMR (400 MHz,CDCl₃) 8.46 (br s, 2H), 7.36 (m, 2H), 7.03 (m, 2H), 5.40 (m, 1H), 1.63(d, J=6.8 Hz, 3H).

Methods 14-15

Following a similar procedure to Method 13, the following compounds weresynthesized from a 2,3,6-trichloro-5-nitropyridine by reacting it withan amine.

Method Product NMR/MS Amine 14 (2R)-2-[(5,6-Dichloro-3- (400 MHz) 8.91(d, J = 7.2 Hz, (R)-2-amino-2- nitropyridin-2-yl)amino]-2- 1H), 8.66 (s,1H), 7.45 (m, 2H), (4-fluoro (4-fluorophenyl)ethanol 7.15 (m, 2H), 5.25(m, 2H), phenyl)ethanol 3.80 (m, 2H) 15 3,6-Dichloro-N-(5- (400 MHz)12.37 (s, 1H), 9.83 (s, 5-cyclopropyl- cyclopropyl-1H-pyrazol-3- 1H),8.54 (s, 1H), 6.27 (s, 1H), 1H-pyrazol-3- yl)-5-nitropyridin-2-amine1.94 (m, 1H), 0.95 (m, 2H), 0.70 (m, amine 2H). MS: Calcd.: 313; Found:[M + H]⁺ 314Method 16

6-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine

To a solution of 2,6-dichloro-3-nitropyridine (0.67 g, 3.2 mmol) andDIEA (0.46 ml, 2.65 mmol) in EtOH (20 ml) was added5-cyclopropyl-1H-pyrazol-3-amine (0.26 g, 2.12 mmol) solution in EtOH (5ml) dropwise at 0° C. After addition, the reaction mixture was stirredat 25° C. for 24 hrs. The solvent was removed under reduced pressure andthe resulted residue was purified by column chromatography(hexane-EtOAc=5:1) to give the title compound as a yellow solid (0.58 g,98%). ¹H NMR (400 MHz) δ12.36 (s, 1H), 10.20 (s, 1H), 8.54 (d, J=8.4 Hz,1H), 7.01 (d, J=8.4 Hz, 1H), 6.39 (d, J=1.6 Hz, 1H), 1.94 (m, 1H), 0.96(m, 2H), 0.71 (m, 2H). MS: Calcd.: 279. Found: [M+H]⁺ 280.

Method 17

5,6-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridine-2-amine

To a solution of 2,3,6-trichloro-5-nitropyridine (1.62 g, 7.10 mmol) andDIEA (1.24 ml, 7.1 mmol) in THF (25 ml) was added dropwise a solution of5-cyclopropyl-1H-pyrazol-3-amine (0.70 g, 5.68 mmol) in THF (5 ml) at 0°C. After addition, the reaction mixture was stirred at 25° C. for 24hours. The solvent was removed under reduced pressure and the resultedresidue was purified by column chromatography (hexane:EtOAc=1.5:1) togive the title compound as a yellow solid (0.83 g, 47%). NMR (400 MHz)12.39 (s, 1H), 10.12 (s, 1H), 8.77 (d, J=1.2 Hz, 1H), 6.35 (s, 1H), 1.95(m, 1H), 0.96 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 313. Found: [M+H]⁺ 314.

Method 18

Following a similar procedure to Method 17, the following compound wassynthesized from a 2,3,6-trichloro-5-nitropyridine by reacting it withthe appropriate amine

Meth Product NMR/MS Amine 1 18 (R)-2-(3,6-Dichloro- (400 MHz) 8.46 (s,1H), 8.22 (d, J = 8.0 Hz, (R)-2-amino-2- 5-nitropyridin-2- 1H), 7.45 (m,2H), 7.16 (m, 2H), 5.22 (m, (4-fluoro ylamino)-2-(4- 1H), 5.05 (t, J =6.0 Hz, 1H), 3.87 (m, 1H), phenyl)ethanol fluorophenyl)ethanol 3.72 (m,1H)Method 19

6-Bromo-N-(4-fluorobenzyl)pyridin-2-amine

To a suspension of 6-bromopyridin-2-amine (500 mg, 2.89 mmol), sodiumtert-butoxide (695 mg, 7.24 mmol) in anhydrous toluene (20 ml) was added4-fluorobenzylchloride (415 mg, 2.90 mmol) at room temperature. Thereaction mixture was heated at 100° C. overnight. EtOAc was added andthe mixture was washed with brine and was concentrated. Flashchromatography (10-14% EtOAc in hexanes) gave the title compound (506mg, 63%). ¹H NMR (CDCl₃) δ 4.40 (m, 2H), 4.95 (br s, 1H), 6.20 (m, 1H),6.73 (m, 1H), 7.00 (m, 2H), 7.25 (m, 3H).

Method 20

6-Chloro-N-[(1S)-1-(4-fluorophenyl)ethyl]pyridin-2-amine

To a 25 ml round bottom flask was added Pd(OAc)₂ (45 mg, 0.2 mmol),(biphenyl-2-ylmethylene)bis(dimethylphosphine) (120 mg, 0.4 mmol) andsodium tert-butoxide (480 mg, 5.0 mmol). The flask was sealed andrefilled with N₂. To the mixture was added a solution of2,6-dichloropyridine (300 mg, 2.0 mmol) and[(1S)-1-(4-fluorophenyl)ethyl]amine (306 mg, 2.2 mmol) in toluene (4ml). The reaction mixture was heated at 85° C. overnight. The solventwas removed and EtOAc was added and the mixture was washed with brineand was concentrated. Flash chromatography (10-40% EtOAc in hexanes)gave the title compound (339 mg, 68%). ¹H NMR (CDCl₃) δ 1.55 (m, 3H),4.66 (m, 1H), 5.07 (br s, 1H), 6.01 (m, 1H), 6.54 (m, 1H), 7.00 (m, 2H),7.25 (m, 3H).

Method 21

tert-Butyl5-cyclopropyl-3-[(6-{[(1S)-1-(4-fluorophenyl)ethyl]amino}pyridin-2-yl)amino]-1H-pyrazole-1-carboxylate

To a 25 ml round bottom flask was added Pd₂(dba)₃ (84 mg, 0.092 mmol),(biphenyl-2-ylmethylene)bis(dimethylphosphine) (55 mg, 0.184 mmol) andsodium tert-butoxide (132 mg, 1.38 mmol). The flask was sealed andrefilled with N₂. To the mixture was added a solution of6-chloro-N-[(1S)-1-(4-fluorophenyl)ethyl]pyridin-2-amine (Method 20; 230mg, 0.92 mmol) and tert-butyl3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate (223 mg, 1.0 mmol) intoluene (4 ml). The reaction mixture was heated at 110° C. overnight.Solvent was removed and EtOAc was added and the mixture was washed withbrine and was concentrated. Flash chromatography (15-40% EtOAc inhexanes) gave the title compound (146 mg, 36%). ¹H NMR (CDCl₃) δ0.80-1.00 (m, 4H), 1.60 (m, 3H), 1.65 (s, 9H), 1.95 (m, 1H), 4.71 (m,1H), 4.75 (m, 1H), 5.75 (m, 1H), 6.09 (m, 1H), 6.21 (s, 1H), 7.00 (m,2H), 7.23 (m, 2H), 7.30 (m, 1H), 9.40 (s, 1H).

Method 22

tert-Butyl(2-{[(6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoro-2-{[(1S)-1-(4-fluorophenyl)ethyl]amino}pyridin-3-yl)methyl]amino}-2-oxoethyl)carbamate

A round bottom flask was charged with(S)-3-(aminomethyl)-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine(Example 3; 0.07 g, 0.18 mmol), 2-(tert-butoxycarbonyl)acetic acidloaded TFP resin (1.15 mmol/g loading, 0.18 mmol), and a THF-DCMsolution (1:1, 4 ml) at 0° C. The resulting solution was shakenvigorously at 0° C. for 2 hrs and filtered. The resulting resin waswashed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). Theresulting organic layers were combined and concentrated. The resultingsolid was purified by reverse-phase column chromatography (5-50% CH₃CNin H₂O over 400 ml) to give the title compound (0.035 g, 35%). MS:Calcd.: 541. Found: [M+H]⁺ 542.

Method 23

(S)-5,6-Difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine

A solution of 2,3,6-trifluoro-5-nitropyridine (Method 24, 2.0 g, 11.2mmol) in THF (50 ml) was cooled to 0° C.(S)-1-(4-Fluorophenyl)ethanamine (1.56 g, 11.2 mmol) was added and thereaction was stirred at 0° C. for 30 minutes. The reaction was quenchedwith water (50 ml) and then extracted with DCM (2×75 ml). The combinedorganic fractions were dried over Na₂SO₄, filtered, and thenconcentrated. The resulting oil was purified by column chromatography(hexane-DCM=1:1) to give the title compound (2.3 g, 70%).

Method 24

2,3,6-Trifluoro-5-nitropyridine

To neat 2,3,6-trifluoropyridine (12.0 g, 90 mmol) was slowly addedfuming HNO₃ (142 g, 2254 mmol) and H₂SO₄ (133 g, 1353 mmol) slow enoughto keep the internal temperature below 40° C. Upon completion of theaddition, the resulting solution was heated to 60° C. for 30 minutes,and then cooled to 0° C. Ice water (21) was added, and the reaction wasextracted with hexanes (2×300 ml) and then DCM (1×300 ml). The combinedorganic fractions were dried over Na₂SO₄, filtered, and concentrated togive the title compound (8.1 g, 50%), which was used without furtherpurification.

Method 25

(S)-2-(5,6-Difluoro-3-nitropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol

A solution of 2,3,6-trifluoro-5-nitropyridine (1.2 g, 6.7 mmol) in THF(40 ml) was cooled to 0° C. (R)-2-amino-2-(4-fluorophenyl)ethanol (1.0g, 6.7 mmol) was then added and the reaction was stirred at 0° C. for 30minutes. The reaction was quenched with water (50 ml) and then extractedwith DCM (2×75 ml). The combined organic fractions were dried overNa₂SO₄, filtered, and then concentrated. The resulting oil was purifiedby column chromatography (DCM-MeOH=100:1) to give the title compound(1.2 g, 57%). The product was carried over to the next step withoutcharacterization.

Method 26

5,6-Dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine

To a mixture of 2,3,6-trichloro-5-nitropyridine (2.61 g, 11.4 mmol) andDIEA (1.90 ml, 11.4 mmol) in THF (50 ml) was added the5-isopropoxy-1H-pyrazol-3-amine (1.20 g, 8.50 mmol) at 0° C. Afteraddition, the reaction mixture was stirred at 25° C. for 5 days. Thesolvent was removed under reduced pressure and the resulting residue waspurified by column chromatography (hexane-EtOAc=2.5:1) to give the titlecompound as a yellow solid (0.77 g, 27%). ¹H NMR (400 MHz) δ 12.26 &11.64 (s, 1H), 10.42 & 10.04 (s, 1H), 8.81 & 8.77 (s, 1H), 6.02 & 5.94(s, 1H), 4.70 & 4.48 (m, 1H), 1.32 (d, J=6.0 Hz, 3H), 1.27 (d, J=6.0 Hz,1H). MS: Calcd.: 331. Found: [M+H]⁺ 332.

Method 27

3,6-Dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridin-2-amine

To a mixture of 2,3,6-trichloro-5-nitropyridine (2.61 g, 11.4 mmol) andDIEA (1.90 ml, 11.4 mmol) in THF (50 ml) was added5-isopropoxy-1H-pyrazol-3-amine (1.20 g, 8.50 mmol) at 0° C. Afteraddition, the reaction mixture was stirred at 25° C. for 5 days. Thesolvent was removed under reduced pressure and the resulted residue waspurified by column chromatography (hexane-EtOAc=1:1) to give the titlecompound as a yellow solid (0.51 g, 18%). ¹H NMR (400 MHz) δ 12.22 &11.35 (s, 1H), 10.12 & 9.80 (s, 1H), 8.64 & 8.54 (s, 1H), 5.95 & 5.84(s, 1H), 4.70 & 4.46 (m, 1H), 1.27-1.32 (m, 6H). MS: Calcd.: 331. Found:[M+H]⁺ 332.

Method 28

6-Chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine

To a solution of 2,6-dichloro-3-nitropyridine (0.51 g, 2.7 mmol) andDIEA (0.39 ml, 2.2 mmol) in THF (10 ml) was added the5-isopropoxy-1H-pyrazol-3-amine (0.25 g, 1.8 mmol) solution at 0° C.After addition, the reaction mixture was stirred at 25° C. for 3 daysand 60° C. for 24 hours. The solvent was removed under reduced pressureand the resulting residue was purified by column chromatography(hexane-EtOAc=3:1) to give the title compound as a yellow solid (0.33 g,63%). ¹H NMR (400 MHz) δ 12.25 & 11.66 (s, 1H), 10.46 & 10.13 (s, 1H),8.58 & 8.55 (d, J=8.8 Hz, 1H), 7.11 & 7.02 (d, J=8.8 Hz, 1H), 6.08 &5.97 (s, 1H), 4.70 & 4.48 (m, 1H), 1.32 & 1.27 (d, J=6.0 Hz, 6H). MS:Calcd.: 297. Found: [M+H]⁺ 298.

Method 29

(R)-2-(6-Chloro-3-nitropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol

To a mixture of 2,6-dichloro-3-nitropyridine (0.933 g, 4.83 mmol) andpotassium carbonate (0.58 g, 4.19 mmol) in anhydrous acetonitrile (10ml) was added (R)-2-amino-2-(4-fluoro phenyl)ethanol (1.00 g, 7.19 mmol)at 0° C. The resulting reaction mixture was stirred at 25° C. for 18hours. The solid was removed by filtration and washed with EtOAc (20ml). After evaporation of the solvent, the resulting residue waspurified by column chromatography (hexane-EtOAc=5:1) to give the titlecompound as a yellow solid (0.77 g, 61%). ¹H NMR (400 MHz) δ 8.96 (d,J=7.6 Hz, 1H), 8.46 (d, J=8.4 Hz, 1H), 7.45 (m, 2H), 7.15 (m, 2H), 6.81(d, J=8.8 Hz, 1H), 5.27 (m, 2H), 3.80 (m, 2H).

Method 30

(S)-6-Chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine

To a mixture of 2,6-dichloro-3-nitropyridine (2.26 g, 10.8 mmol) andpotassium carbonate (1.29 g, 9.34 mmol) in anhydrous CH₃CN (20 ml), wasadded (S)-1-(4-fluoro-phenyl)-ethylamine (1.00 g, 7.19 mmol) dropwise at0° C. The reaction mixture was stirred at 25° C. for 17 hours. The solidwas removed by filtration and the resulted cake was washed with EtOAc(20 ml). The combined filtrate was concentrated and purified by columnchromatography (hexane-EtOAc=10:1) to give the title compound as ayellow solid (1.74 g, 82%). ¹H NMR (400 MHz) δ 8.65 (d, J=7.6 Hz, 1H),8.43 (d, J=8.4 Hz, 1H), 7.51 (m, 2H), 7.16 (m, 2H), 6.81 (d, J=8.8 Hz,1H), 5.37 (m, 1H), 1.59 (d, J=6.8 Hz, 3H).

Method 31

N-(5-Cyclopropyl-1H-pyrazol-3-yl)-3,6-difluoropyridin-2-amine

A solution of tert-butyl 5-amino-3-cyclopropyl-1H-pyrazole-1-carboxylate(1.00 g, 4.49 mmol) in THF (15 ml) was cooled to −78° C. t-BuLi (1.7 Min THF, 4.15 mmol) was added dropwise and the resulting solution wasstirred for 30 min. at −78° C. A solution of 2,3,6-trifluoropyridine(0.46 g, 3.4 mmol) in THF (5 ml) was added, and the resulting solutionwas stirred for 5 min at −78° C., and then the reaction was warmed to 0°C., and stirred at that temperature for 30 min. The reaction wasquenched with aq. NH₄Cl and extract with EtOAc (2×20 ml). The organicfractions were dried over Na₂SO₄, filtered, and concentrated. Theresulting oil was then placed in ACN (15 ml) at 0° C., andN-trimethylsilylimidazole (0.5 ml) was added. The reaction was stirredfor 20 min, and then concentrated. The resulting oil was purified bycolumn chromatography (DCM-MeOH=100:1) to give the title compound (0.10g, 12%). MS: Calcd.: 236. Found: [M+H]⁺ 237.

Method 32

6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-2,5-difluoronicotinonitrile

A solution of 2,5,6-trifluoronicotinonitrile (30.0 g, 189.8 mmol) in ACN(240 ml) was prepared in a 1l 3-neck flask at room temperature and thencooled to −5° C. using an ice-salt bath. An addition funnel containingtriethylamine (29.1 ml, 208.8 mmol) and a second addition funnelcontaining a solution of 5-cyclopropyl-1H-pyrazol-3-amine (25.7 g, 208.8mmol) in ACN (160 ml) were placed on top of the reaction flask. A totalof 5 ml of triethylamine was added quickly dropwise to the reaction. Thereaction was allowed to stir for min, followed by the simultaneousdropwise addition of the remaining triethylamine and5-cyclopropyl-1H-pyrazol-3-amine solution at a rate slow enough to keepthe internal temperature at or below 5° C. Upon completion of theaddition, the reaction was allowed to stir for 1 hour at 0° C., at whichpoint no starting material remained, and the reaction was filteredthrough a fritted funnel. The remaining solids were washed with 0° C.ACN (3×100 ml). The solid product was then dried under vacuum for 30minutes to give the title compound (25.2 g, 51%) which was used withoutfurther purification. ¹H NMR (400 MHz, CD₃OD) δ 7.81-7.77 (m, 1H), 6.33(s, 1H), 1.91 (septet, 1H), 0.99-0.98 (m, 2H), 0.76-0.73 (m, 2H). MS:Calcd.: 261. Found: [M+H]⁺ 262.

Method 33

(S)-1-(5-Fluoropyridin-2-yl)ethanamine

To the solution of (S)-tert-butyl-1-(5-fluoropyridin-2-yl)ethylcarbamate(Method 34, 12.8 g, 53.3 mmol) in DCM (100 ml) was added HCl/dioxanesolution (107 ml, 4 N, 428 mmol). The reaction was stirred at roomtemperature for 3 hours. The solvent was removed and 50 ml of saturatedsodium bicarbonate was added. The resulting aqueous solution wasextracted with ether (6×400 ml), dried over sodium sulfate andconcentrated to give the title compound (7.30 g, 98%) as pale yellowoil. ¹H NMR (400 MHz) δ 8.44 (d, J=2.8 Hz, 1H), 7.66 (m, 1H), 7.53 (m,1H), 4.01 (q, J=6.8 Hz, 1H), 1.94 (b, 2H), 1.26 (d, J=6.8 Hz, 3H). MS:Calcd.: 140. Found: [M+H]⁺ 141.

Method 34

(S)-tert-Butyl-1-(5-fluoropyridin-2-yl)ethylcarbamate

The solution of (S)—N-(1-(5-fluoropyridin-2-yl)ethyl)acetamide (Method35, 11.0 g, 60.37 mmol), DMAP (1.48 g, 12.07 mmol) and Boc₂O (26.35 g,120.7 mmol) in THF (100 ml) was stirred at 50° C. for 20 hours. Aftercooled to room temperature, lithium hydroxide monohydrate (5.19 g, 123.8mmol) and water (100 ml) were added. The reaction was stirred at roomtemperature for 5 hours and diluted with ether (200 ml). The organiclayer was separated, washed with brine (100 ml), and dried over sodiumsulfate. After removal of solvent, the resulted residue was purified bycolumn chromatography (Hexane-EtOAc=5:1) to give the title compound as apale yellow oil (13.6 g, 94%). ¹H NMR (400 MHz) δ 8.46 (d, J=2.8 Hz,1H), 7.69 (m, 1H), 7.35-7.41 (m, 2H), 4.67 (m, 1H), 1.37 (s, 9H), 1.32(d, J=7.2 Hz, 3H). MS: Calcd.: 240. Found: [M+H]⁺ 241.

Method 35

(S)—N-(1-(5-Fluoropyridin-2-yl)ethyl)acetamide

N-(1-(5-fluoropyridin-2-yl)vinyl)acetamide (Method 36, 11.0 g, 61.1mmol) in MeOH (120 ml) under N₂ was added(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.441 g, 0.611mmol). The solution was transferred to a high pressure bomb and charged150 psi H₂. The reaction stirred at room temperature and maintainedinside pressure between 120-150 psi for 7 hours. The solvent was removedand the resulted residue was purified by column chromatography (EtOAc)to give the title compound as a white solid (9.8 g, 88%). ¹H NMR (400MHz) δ 8.49 (d, J=2.4 Hz, 1H), 8.32 (d, J=7.6 Hz, 1H), 7.66 (m, 1H),7.39 (dd, J=4.4 and 8.8 Hz, 1H), 4.95 (m, 1H), 1.85 (s, 3H), 1.34 (d,J=7.2 Hz, 3H). MS: Calcd.: 182. Found: [M+H]⁺ 183. Enantiomeric excessdetermined by HPLC (Chiralpak IA; 70:30 CO₂/MeOH), 95.3% ee.

Method 36

N-(1-(5-Fluoropyridin-2-yl)vinyl)acetamide

A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with170 ml of anhydrous THF and cooled to 0° C. 5-Fluoropicolinontrile(Method 37, 53.6 g, 425.82 mmol) in THF (170 ml) was added dropwise. Thereaction was stirred at 0° C. for 30 minutes, then diluted with DCM (170ml). Acetic anhydride (48.3 ml, 510.98 mmol) in DCM (100 ml) was addeddropwise at 0° C. After addition, the reaction was warmed to roomtemperature and stirred at room temperature for 8 hours. Saturatedsodium bicarbonate solution (50 ml) was added and extracted with EtOAc(2×200 ml). The combined organic was dried over sodium sulfate. Afterremoval of solvent, the resulted residue was purified by columnchromatography (hexane-EtOAc=2.5:1) to give the title compound as awhite solid (26.6 g, 35%). ¹H NMR (400 MHz) δ 9.37 (s, 1H), 8.57 (d,J=2.8 Hz, 1H), 7.81 (m, 2H), 6.01 (s, 1H), 5.52 (s, 1H), 2.08 (s, 3H).MS: Calcd.: 180. Found: [M+H]⁺ 181.

Method 37

5-Fluoropicolinontrile

2-Bromo-5-fluoropyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol),zinc cyanide (40.3 g, 343 mmol), diphenylphosphinoferrocene (11.7 g,21.1 mmol) and Pd₂ dba₃ (9.68 g, 10.6 mmol) in anhydrous DMA (300 ml)was heated at 95° C. for 3 hours. After cooled to room temperature,brine (100 ml) and ether (500 ml) was added. The solid formed wasremoved by filtration and washed with ether (300 ml). The organic layerwas separated, washed with brine (200 ml) and dried over sodium sulfate,and concentrated. After removal of solvent, the resulted residue waspurified by column chromatography (hexane-DCM=1:1) to give the titlecompound as a white solid (49 g, 72%). ¹H NMR (400 MHz) δ 8.82 (d, J=2.8Hz, 1H), 8.21 (dd, J=4.4 and 8.8 Hz, 1H), 8.05 (dd, J=2.8 and 8.8 Hz,1H).

Method 38

6-Fluoro-N-methoxy-N-methylnicotinamide

To a solution of 6-fluoronicotinic acid (10 g, 70.9 mmol) in DCM (200ml), was added N,O-Dimethylhydroxylamine hydrochloride (7.3 g, 74.8mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (15g, 78.5 mmol), and triethylamine (22 ml, 156 mmol). The reaction mixturewas allowed to stir at room temperature for 16 hours. The reaction waspartitioned with water, layers were cut, and organic layer was driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude residueobtained was purified by a silica gel filtration using EtOAc-DCM (4:1)to give 7.2 g (55% isolated yield) of the title compound. ¹H NMR: 8.48(s, 1H) 8.21 (t, J=8.29 Hz, 1H) 7.27 (dd, J=8.29, 3.01 Hz, 1H) 3.54 (s,3H) 3.27 (s, 3H).

Method 39

2-Chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-4-iodonicotinonitrile

The crude 2,6-dichloro-5-fluoro-4-iodonicotinonitrile (8.0 g, 25.2mmol), Et₃N (3.3 g, 32.8 mmol) and 5-cyclopropyl-1H-pyrazol-3-amine (3.1g, 25.2 mmol) were placed in ACN (50 ml) and the resulting solution washeated to 80° C. for 24 hours. The reaction was cooled to roomtemperature, filtered, and the resulting solid was washed with cold ACN,dried, and collected to give the title compound (3.0 g, 29%). MS:Calcd.: 403. Found: [M+H]⁺ 404.

Method 40

2,6-Dichloro-5-fluoro-4-iodonicotinonitrile

To a solution of diisopropylamine (15.9 g, 157 mmol) in THF (400 ml) at−78° C. was added n-butyllithium (2.5 M hexanes, 154 mmol), and thesolution was stirred at −78° C. for 30 minutes. The lithiumdiisopropylamide solution was then added slowly dropwise to a −78° C.solution of 2,6-dichloro-5-fluoronicotinonitrile (10.0 g, 52.3 mmol) andiodine (26.5 g, 104 mmol) in THF (175 ml). Upon completion of theaddition, the reaction was allowed to warm slowly to room temperature,and stirred at room temperature for 12 hours. An aqueous 10% Na₂S₂O₃solution (500 ml) was added and the reaction was extracted with EtOAc(3×300 ml). The combined organic fractions were dried over Na₂SO₄,filtered, and then concentrated to give the title compound (14.5 g, 87%)as a brown solid that was used without further purification.

Method 41

2,5-Difluoro-6-(5-methyl-1H-pyrazol-3-ylamino)nicotinonitrile

To a solution of 2,5,6-trifluoronicotinonitrile (1.0 g, 6.3 mmol) andtriethylamine (0.83 g, 8.2 mmol) in ACN (30 ml) at 0° C. was added5-methyl-1H-pyrazol-3-amine (0.67 g, 6.9 mmol). The reaction was stirredat 0° C. for 1 hour, at which point the reaction was filtered. Theresulting solid was washed with cold ACN, dried and collected to givethe title compound (0.44 g, 29%). MS: Calcd.: 235. Found: [M+H]⁺ 236.

Method 42

2,5-Difluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile

To a solution of 2,5,6-trifluoronicotinonitrile (3.0 g, 19.0 mmol) andtriethylamine (2.5 g, 24.7 mmol) in ACN (30 ml) at 0° C. was added5-isopropoxy-1H-pyrazol-3-amine (2.95 g, 20.9 mmol) in ACN (15 ml). Thereaction was stirred at 0° C. for 1 hour, at which point the reactionwas diluted with water (50 ml) and extracted with DCM (2×50 ml). Thecombined organic fractions were dried over Na₂SO₄, filtered, and thenconcentrated. The resulting oil was purified by column chromatography(DCM-MeOH=100:1) to give the title compound (0.48 g, 9%). MS: Calcd.:279. Found: [M+H]⁺ 280.

Method 42 (Alternative Procedure)

2,5-Difluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile

tert-Butyl5-(5-cyano-3,6-difluoropyridin-2-ylamino)-3-isopropoxy-1H-pyrazole-1-carboxylate(Method 79, 10.6 g, 27.9 mmol), was placed in DCM (500 ml) at roomtemperature. A 4.0 M solution of HCl (16.3 g, 447 mmol) in dioxane wasadded dropwise, and upon completion of the addition the reaction wasallowed to stir for an additional 30 minutes. The reaction wasconcentrated to dryness, and dissolved in DCM (300 ml) with a minimalamount of MeOH (5 ml) to aid solubility. A saturated aqueous solution ofNa₂CO₃ (300 ml) was added, and the reaction was stirred vigorously for30 minutes. The layers were allowed to separate, and the organicfraction was dried (Na₂SO₄), filtered, and concentrated. The resultingresidue was slurried with cold DCM (approx. 50 ml), filtered, and theremaining solid was washed with DCM and dried to give the title compound(5.5 g, 70%). MS: Calcd.: 279. Found: [M+H]⁺ 280.

Method 43

2,5-Dichloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)nicotinonitrile

To a solution of 2,5,6-trichloronicotinonitrile (Method 44, 1.0 g, 4.8mmol) and DIEA (0.81 g, 6.2 mmol) in n-BuOH (5 ml) was added5-cyclopropyl-1H-pyrazol-3-amine (2.3 g, 19.3 mmol). The reaction washeated to 60° C. for 2 hours, at which point the reaction was cooled toroom temperature and concentrated. The resulting residue was dilutedwith 10 ml ACN, and stored at 0° C. for 1 hour. The solids that formedwere then filtered, washed with cold ACN, dried and collected to givethe title compound (0.62 g, 43%). MS: Calcd.: 294. Found: [M+H]⁺ 295.

Method 44

2,5,6-Trichloronicotinonitrile

A suspension of 2,5,6-trichloronicotinamide (Method 45, 2.3 g, 10.2mmol) in POCl₃ (20 ml) was heated to 90° C. for 1 hour. The reaction wasthen cooled to room temperature, and the POCl₃ was removed under vacuum.The resulting residue was taken up in DCM (50 ml) and ice water (50 ml)was then added, followed by the careful addition of an aqueous solutionof Na₂CO₃ until pH 8 was achieved. The organic fraction was then driedover Na₂SO₄, filtered, and concentrated to give the title compound (2.1g, 80%) which was used without further purification. ¹H NMR (400 MHz,CD₃OD) δ 8.54 (s, 1H).

Method 44 (Alternative Procedure)

2,5,6-Trichloronicotinonitrile

To a solution of 2,4,5,6-tetrachloronicotinonitrile (7.6 g, 31.4 mmol)in MeOH/THF (230 ml/230 ml) was added zinc dust (4.0 g, 62.8 mmol)slowly at 0° C. and the saturated NH₄Cl solution (105 ml) and themixture was stirred for 30 minutes. TLC indicated that the reaction iscomplete. Saturated NH₄OAc solution (180 ml) was added to the mixtureand the mixture was allowed to stir at room temperature for 30 minutes.The mixture was filtered and was washed with EtOAc (500 ml). Thefiltrate was washed with brine and dried and concentrated to give asolid. ISCO column purification gave the title compound (4.63 g, 71%).¹H NMR (CDCl₃): δ 8.97 (s, 1H).

Method 45

2,5,6-Trichloronicotinamide

A solution of 2,5,6-trichloronicotinoyl chloride (Method 46, 2.5 g, 10.2mmol) in dioxane (20 ml) was added dropwise to 10 ml ammonium hydroxide(28% NH₃ in water) at 0° C. Upon completion of the addition, thereaction was allowed to stir for an additional 10 minutes, and thenextracted with DCM (3×50 ml). The combined organic fractions were driedover Na₂SO₄, filtered, and concentrated to give the title compound (2.3g, 100%), which was used without further purification.

Method 46

2,5,6-Trichloronicotinoyl chloride

To a suspension of 2,5,6-trichloronicotinic acid (Method 47, 2.3 g, 10.2mmol) in DCM (25 ml) at room temperature was added oxalyl chloride (3.0g, 24.4 mmol) and 3 drops of dry DMF. After 30 minutes, the resultingclear solution was concentrated to dryness to give the title compound(2.5 g, 100%), which was immediately used without further purification.

Method 47

2,5,6-Trichloronicotinic acid

A suspension of 2,3,6-trichloro-5-methylpyridine (Method 48, 11.8 g,60.0 mmol) in water (400 ml) was heated to 100° C. Portionwise, KMnO₄(28.5 g, 180.2 mmol) was then added over 12 hours. The reaction was thenallowed to stir for 2 days at 100° C., over which time an additional 10g of KMnO₄ was added portionwise. When no starting material remained,the hot reaction was filtered, washed with hot water (2×75 ml), and theresulting filtrate was allowed to cool to room temperature. The aqueousfiltrate was then extracted with EtOAc (3×100 ml), and then concentratedto a 50 ml volume. This aqueous solution was then cooled to 0° C. andadjusted to pH 1-2 with 6.0 M HCl. The resulting solid was thencollected by filtration, washed with cold water, and dried to give thetitle compound (2.5 g, 18%) that was used without further purification.

Method 48

2,3,6-Trichloro-5-methylpyridine

A well powdered mixture of 3-methylpiperidine-2,6-dione (Method 49, 15.0g, 118 mmol) and PCl₅ (155.0 g, 743 mmol) was slowly heated to 150° C.and kept at that temperature for 2 hours. The resulting solution wasthen cooled to room temperature, and slowly poured onto ice. Theresulting precipitate was filtered, washed with cold water, and dried.The resulting precipitate was then recrystallized from a mixture ofEtOH-petroleum ether (1:8) to give the title compound (11.8 g, 51%).

Method 49

3-Methylpiperidine-2,6-dione

A solution of H₂SO₄ (80 ml), acetic acid (500 ml) and2-methylpentanedinitrile (128.0 g, 1184 mmol) was stirred at roomtemperature. An aqueous solution of acetic acid (100 ml in 32 ml water)was then added dropwise. Upon completion of the addition, the reactionwas heated to 130° C. for 1 hour. The reaction was then allowed to coolto room temperature and filtered to remove solids, which were washedwith acetic acid (100 ml). The filtrate was then concentrated until aresidue resulted. This residue was poured into water (0.75 l), andadjusted to pH 5 with Na₂CO₃. The resulting solid was collected byfiltration and washed with cold water to give the title compound (101 g,67%) which was used without further purification.

Method 50

(S)-1-(3,5-Difluoropyridin-2-yl)ethanamine

To a solution of(S)-tert-butyl-1-(3,5-difluoropyridin-2-yl)ethylcarbamate (Method 51,2.05 g, 7.94 mmol) in DCM (15 ml) was added HCl/dioxane (15.9 ml, 4 N,63.5 mmol). The reaction was stirred at room temperature for 3 hours.The solvent was removed and 10 ml of saturated sodium bicarbonate wasadded. The resulting aqueous solution was extracted with ether (5×100ml), dried over sodium sulfate and concentrated to give the titlecompound (1.1 g, 88%) as a pale yellow oil. ¹H NMR (400 MHz) δ 8.46 (d,J=2.0 Hz, 1H), 7.85 (m, 1H), 4.23 (q, J=6.8 Hz, 1H), 1.90 (b, 2H), 1.27(d, J=6.8 Hz, 3H). MS: Calcd.: 158. Found: [M+H]⁺ 159.

Method 51

(S)-tert-Butyl-1-(3,5-difluoropyridin-2-yl)ethylcarbamate

A solution of (S)—N-(1-(3,5-difluoropyridin-2-yl)ethyl)acetamide (Method52, 2.0 g, 9.99 mmol), DMAP (0.244 g, 2.00 mmol), and Boc₂O (6.54 g,30.0 mmol) in THF (20 ml) was stirred at 50° C. for 40 hours. Aftercooling to room temperature, lithium hydroxide monohydrate (0.671 g,16.0 mmol) and water (20 ml) were added. The reaction was stirred atroom temperature for 18 hours. To which was added ether (100 ml). Theorganic layer was separated, washed with brine (50 ml) and dried oversodium sulfate. After removal of solvent, the resulted residue waspurified by column chromatography (hexane-EtOAc=5:1) to give the titlecompound as a colourless oil (2.05 g, 79%). ¹H NMR (400 MHz) δ 8.45 (s,1H), 7.87 (m, 1H), 7.24 (d, J=7.6 Hz 1H), 4.92 (m, 1H), 1.34 (s, 9H),1.32 (d, J=7.2 Hz, 3H). MS: Calcd.: 258. Found: [M+H]⁺ 259. Enantiomericexcess was determined by HPLC (Chiralpak ADH; 98:2 CO₂/MeOH), 93.6% ee.

Method 52

(S)—N-(1-(3,5-Difluoropyridin-2-yl)ethyl)acetamide

To a solution of N-(1-(3,5-difluoropyridin-2-yl)vinyl)acetamide (Method53, 2.2 g, 11.1 mmol) in MeOH (20 ml) under N₂ was added(+)-1,2-bis((2S,5S)-2,5-dimethyl phospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.074 g, 0.111mmol). The solution was transferred to a high-pressure bomb and charged150 psi H₂. The reaction stirred at room temperature and maintainedinside pressure between 120-150 psi for 24 hours. The solvent wasremoved and the resulted residue was purified by column chromatography(EtOAc) to give the title compound as a white solid (2.0 g, 90%). ¹H NMR(400 MHz) δ 8.47 (d, J=2.4 Hz, 1H), 8.34 (d, J=7.2 Hz, 1H), 7.89 (m,1H), 5.21 (m, 1H), 1.81 (s, 3H), 1.34 (d, J=6.8 Hz, 3H). MS: Calcd.:200. Found: [M+H]⁺ 201.

Method 53

N-(1-(3,5-Difluoropyridin-2-yl)vinyl)acetamide

To a mixture of (Z)-1-(3,5-difluoropyridin-2-yl)ethanone oxime (Method54, 12.5 g, 72.6 mmol), acetic anhydride (54.8 ml, 581 mmol), and ironpowder (32.4 g, 581 mmol) in DMF (100 ml) was added TMSCl (0.01 ml,0.073 mmol). The reaction mixture was stirred at room temperature for 18hours, then diluted with ether (300 ml) and filtered through a short padof celite. The filtrate was concentrated and the residue was partitionedbetween 200 ml of EtOAc and 50 ml of saturated sodium bicarbonate. Theorganic layer was separated and dried over sodium sulfate. After removalof solvent, the resulted residue was purified by column chromatography(hexane-EtOAc=2:1) to give the title compound as a white solid (2.70 g,19%). ¹H NMR (400 MHz) δ 9.55 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 7.97 (m,1H), 5.87 (s, 1H), 5.14 (s, 1H), 1.99 (s, 3H). MS: Calcd.: 198. Found:[M+H]⁺ 199.

Method 54

(Z)-1-(3,5-Difluoropyridin-2-yl)ethanone oxime

To a solution of 3,5-difluoropicolinonitrile (10.0 g, 71.4 mmol) in THF(200 ml) was added methylmagnesium bromide (61.2 ml, 85.7 mmol) in THFsolution at 0° C. The reaction was stirred at room temperature for 1.5hours. Saturated sodium bicarbonate solution (50 ml) was added,extracted with ether (100 ml), and dried over sodium sulfate. Thesolvent was removed. The residue (11.2 g, 71.28 mmol), hydroxylaminehydrochloride (9.907 g, 142.6 mmol) and sodium acetate (11.70 g, 142.6mmol) in EtOH (100 ml) and water (50 ml) was heated at reflux for 3hours. The solvent was removed and diluted with 50 ml of saturatedsodium bicarbonate and extracted with EtOAc (2×200 ml). After dried oversodium sulfate, the solvent was removed and the title compound was useddirectly in next step without purification.

Method 55

(S)-1-(5-Fluoropyrimidin-2-yl)ethanamine

To a solution of (S)-tert-butyl-1-(5-fluoropyrimidin-2-yl)ethylcarbamate(Method 56, 0.21 g, 0.87 mmol) in DCM (5 ml) was added HCl (1.3 ml, 5.2mmol) in dioxane. The reaction was stirred at room temperature for 3hours. The solvent was removed give(S)-1-(5-fluoropyrimidin-2-yl)ethanamine as HCl salt as white solid(quantitative). MS: Calcd.: 141. Found: [M+H]⁺ 142.

Method 56

(S)-tert-Butyl-1-(5-fluoropyrimidin-2-yl)ethylcarbamate

(S)—N-(1-(5-fluoropyrimidin-2-yl)ethyl)acetamide (Method 57, 0.20 g,1.09 mmol), DMAP (0.027 g, 0.22 mmol) and Boc₂O (0.60 g, 2.73 mmol) inTHF (10 ml) was stirred at 50° C. for 40 hours. After cooled to roomtemperature, lithium hydroxide monohydrate (0.094 g, 2.24 mmol) andwater (10 ml) was added. The reaction was stirred at room temperaturefor 9 hours. Ether (30 ml) was added, organic layer was separated,washed with brine (20 ml) and dried over sodium sulfate. After removalof solvent, the resulted residue was purified by column chromatography(Hex-EtOAc=5:1) to give the title compound as a pale yellow oil (0.21 g,80%). ¹H NMR (400 MHz) 8.84 (s, 2H), 7.24 (d, J=7.6 Hz, 1H), 4.74 (m,1H), 1.35 (s, 12H). MS: Calcd.: 241. Found: [M+H]⁺ 242.

Method 57

(S)—N-(1-(5-Fluoropyrimidin-2-yl)ethyl)acetamide

N-(1-(5-Fluoropyrimidin-2-yl)vinyl)acetamide (Method 58, 0.10 g, 0.55mmol) in MeOH (5 ml) under N₂ was added (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.04 g, 0.0055mmol). The solution was transferred to a high pressure bomb and charged150 psi H₂. The reaction stirred at room temperature for 4 hours. Thesolvent was removed and the resulted residue was purified by columnchromatography (EtOAc) to give the title compound as a white solid(0.096 g, 95%). ¹H NMR (400 MHz) 8.84 (d, J=0.8 Hz, 2H), 8.34 (d, J=7.6Hz, 1H), 5.00 (m, 1H), 1.84 (s, 3H), 1.37 (d, J=6.8 Hz, 3H). MS: Calcd.:183. Found: [M+H]⁺ 184. Enantiomeric excess determined by HPLC(Chiralpak IA; 95:5 CO₂/MeOH), >99% ee.

Method 58

N-(1-(5-Fluoropyrimidin-2-yl)vinyl)acetamide

5-Fluoropyrimidine-2-carbonitrile (Method 59, 1.0 g, 8.1 mmol) in THF(10 ml) was added a solution of MeMgBr (3.3 ml, 9.75 mmol) in ether dropwise at 0° C. After addition, the reaction was warmed to roomtemperature, stirred at room temperature for 1 hour and then dilutedwith DCM (10 ml). Acetic anhydride (1.23 ml, 13.0 mmol) was added in oneportion. The reaction was stirred at room temperature for 1 hour and 40°C. for 1 hour. Saturated sodium bicarbonate solution (10 ml) was addedand extracted with EtOAc (2×20 ml). The combined organic was dried oversodium sulfate. After removal of solvent, the resulted residue waspurified by column chromatography (hexane-EtOAc=2.5:1) to give the titlecompound as a white solid (0.38 g, 26%). ¹H NMR (400 MHz) 9.34 (s, 1H),8.95 (s, 2H), 6.25 (s, 1H), 6.03 (s, 1H), 2.11 (s, 3H). MS: Calcd.: 181.Found: [M+H]⁺ 182.

Method 59

5-Fluoropyrimidine-2-carbonitrile

A 10 ml microwave vial was charged with 2-chloro-5-fluoropyrimidine (2.0g, 15.09 mmol), Pd₂(dba)₃ (0.549 g, 0.6 mmol), DPPF (0.67 g, 1.21 mmol),zinc cyanide (1.15 g, 9.81 mmol), and zinc dust (0.237 mg, 3.62 mmol).The flask was evacuated and backfilled with N₂, and anhydrousdimethylacetamide. The vial was mounted onto a Personal Chemistrymicrowave reactor and heated at 100° C. for 10 hours. The reactionmixture was diluted with EtOAc and then washed with brine three times.The organic layer was obtained and evaporated to dryness. The driedresidue was purified by silica gel chromatography (By ISCO Combiflashwith gradient EtOAc and hexanes) to afford the title compound as acreamy solid (1.50 g, 80%). GC-MS: 123 (M); ¹H NMR (CDCl₃) δ 8.80 (s,2H).

Method 60

2,5-Dichloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]nicotinonitrile

To a 25-ml, round-bottom flask, was added 2,5,6-trichloronicotinonitrile(Method 44, 1 g, 4.8 mmol), 5-methyl-1H-pyrazol-3-amine (466 mg, 4.8mmol), DIEA (1.1 ml, 6.3 mmol), and EtOH (5 ml) and set to heat at 55°C. for 16 hours. The resulting mixture was then purified by silica gelchromatography (Biotage Horizon System) using 25-75% EtOAc/hexanes togive 770 mg of the title compound. ¹H NMR: 12.36 (s, 1H) 9.68 (s, 1H)8.39 (s, 1H) 6.32 (s, 1H) 2.29 (s, 3H). MS: Calcd.: 268. Found: [M+H]⁺267/269.

Method 61

N-[5-(1-Aminoethyl)-2-fluorophenyl]methanesulfonamide

N-{2-Fluoro-5-[(1Z)-N-hydroxyethanimidoyl]phenyl}methanesulfonamide(Method 62, 200 mg, 812 μmol) was dissolved in 15 ml THF, to which wasadded Raney nickel 2800 slurry in water (200 μl). The mixture wascharged with nitrogen and stirred over 1 atm of hydrogen. After 1 hour,MeOH (4 ml) was added and the reaction mixture was stirred overnight.The following morning the solution was filtered through celite, and thecake washed with MeOH, and the organic layer was concentrated to ayellow solid which was dried under high vacuum (181 mg, 96%). ¹H NMR:1.26 (d, 3H, CH₃), 2.92 (s, 3H, SO₂Me), 3.33 (HOD), 4.04 (q, 1H, CH),5.70 (br, 2H, NH₂), 7.06-7.16 (m, 2H, Ar), 7.35 (m, 1H, Ar). LC/MS: 0.79min, 231.08 (M−H)⁻.

Method 62

N-{2-Fluoro-5-[(1Z)-N-hydroxyethanimidoyl]phenyl}methanesulfonamide

In a 100 ml Round bottom flask was added.N-(5-acetyl-2-fluorophenyl)methanesulfonamide (Method 63, 1.41 g, 6.10mmol), hydroxylamine hydrochloride (847 mg, 12.2 mmol), sodium acetate(1.25 g, 15.24 mmol) and 30 ml water. The mixture was heated to 50° C.and then 10 ml EtOH was added to dissolve the contents. The mixture wascontinued heating at 50° C. for 1 hour, then fitted with a refluxcondenser and refluxed at 80° C. for 2 hours. (note: the solution turnshomogeneous at 80° C.). The solution was cooled to room temperature(note: crystals develop), rotovapped to remove traces of EtOH, cooled onan ice bath and filtered off-white crystals. The crystalline product waswashed with ice cold water and air dried to obtain the white crystallineproduct (1.47 g, 98%.) TLC (1:1 Hexanes:EtOAc): R_(f) 0.50. ¹H NMR: 2.12(s, 3H, Me), 3.02 (s, 3H, SO₂Me), 3.32 (HOD), 7.29 (m, 1H, Ar), 7.48 (m,1H, Ar), 7.68 (m, 1H, Ar), 9.67 (s, 1H, NH), 11.31 (s, 1H, OH). LC/MS:1.70 min, 247.04 (M+1)⁺.

Method 63

N-(5-Acetyl-2-fluorophenyl)methanesulfonamide

3-Amino-4-fluoroacetophenone (Method 64, 1.00 g, 6.53 mmol) and pyridine(503 μl, 6.53 mmol) were stirred in 10 ml DCM over a blanket of nitrogenat 0° C. Methanesulfonylchloride (505 μl, 6.53 mmol) was added dropwiseand the reaction was stirred at 0° C. for 5 minutes and warmed to roomtemperature and stirred for 3 hours. Quenched with 30 ml 1N HCl, andextracted with 30 ml DCM. Washed organic layer with Brine, dried overNa₂SO₄ and concentrated to orange oil, and dried under high vacuum.Yellow solid/crystals develop which were triturated with hexanes,redissolved in DCM and evaporated and dried under high vacuum to obtainan off-white/yellow solid (1.42 g, 94%.) TLC (1:1 Hexanes:EtOAc): R_(f)0.46. ¹H NMR (CDCl₃): δ 2.60 (s, 3H, COMe), 3.08 (s, 3H, SO₂Me), 6.56(br, 1H, NH), 7.23 (dd, 1H, Ar), 7.81 (m, 1H, Ar), 8.16 (m, 1H, Ar).LC/MS: 1.66 min, 230.08 (M−1)⁻

Method 64

3-Amino-4-fluoroacetophenone

In a 250 ml round bottom flask was added 3-nitro-4-Fluoroacetophenone(5.00 g, 27.3 mmol) and HCl (12M, 13 ml.) The solution was cooled to 0°C. on an ice bath, and SnCl₂ (15.5 g, 81.9 mmol) dissolved in 20 ml ofwater, was added dropwise over a 15 minute period. (Note: The referencematerial indicates the reaction is exothermic after 1 equivalentaddition of Tin Chloride.) After complete addition the reaction mixturewas stirred at 0° C. for 10 min, warmed to room temp, brought to refluxfor 15 minutes, cooled back to room temp and stirred for 2 hours. Themixture was poured over ice (150 g) and adjusted to pH 12 with 50% NaOHat 0° C. The resulting yellow emulsion was extracted with ether (2×150ml), washed with brine (1×30 ml), dried over sodium sulfate andconcentrated to a yellow solid. The solid was triturated with hexanesand dried to obtain a yellow solid (3.61 g, 86%). TLC (1:1Hexanes:EtOAc): R_(f) 0.63. ¹H NMR (CDCl₃): δ 7.44 (m, 1H, Ar), 7.34 (m,1H, Ar), 7.04 (m, 1H, Ar), 4.32 (br, 2H, NH), 2.54 (s, 3H, Me). LC/MS1.67 min, 154.07 (M+1)⁺

Method 65

1-(6-Fluoropyridin-3-yl)ethanone

To a cold solution (−78° C.) of 6-fluoro-N-methoxy-N-methylnicotinamide(Method 38, 7.2 g, 39 mmol) in THF (130 ml), was added methyl magnesiumbromide (20 ml, 59 mmol, 3M solution in ether) dropwise. The coolingbath was removed and reaction mixture was allowed to warm to roomtemperature and stir for 2 hours. The reaction was quenched with 3N HClsolution, layers were cut, and organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo to afford 3.8 g (70% yield) of thetitle compound. ¹H NMR (CDCl₃) δ 8.80 (s, 1H) 8.29-8.43 (m, 1H)6.98-7.06 (m, 1H) 2.62 (s, 3H).

Method 66

N-[5-(1-Aminoethyl)-2-fluorophenyl]acetamide

To a round, bottom flask was addedN-{2-fluoro-5-[(1Z)-N-hydroxyethanimidoyl]phenyl}acetamide (Method 67,715 mg, 3.4 mmol) and AcOH (0.5 ml) in EtOH (20 ml), followed by theaddition of Palladium on carbon (146 mg, 10 wt %) under N₂ atmosphere.Once the catalyst was added, the system was evacuated and purged withhydrogen (atmospheric pressure). This process was performed severaltimes to ensure complete saturation of hydrogen to the system. Thereaction was then allowed to stir for 16 hours at room temperature. Theheterogeneous mixture was then filtered over a pad of Celite and thefiltrate was concentrated in vacuo to give quantitative yield of thetitle compound. ¹H NMR: 9.67 (s, 1H) 7.80 (d, J=7.54 Hz, 1H) 7.07-7.19(m, 2H) 4.00 (q, J=6.28 Hz, 1H) 2.06 (s, 3H) 1.15-1.30 (m, 3H).

Method 67

N-{2-Fluoro-5-[(1Z)-N-hydroxyethanimidoyl]phenyl}acetamide

To a round, bottom flask was added N-(5-acetyl-2-fluorophenyl)acetamide(Method 68, 1.17 g, 6 mmol), hydroxyl amine hydrochloride salt (834 mg,12 mmol), and NaOAc (1.2 g, 15 mmol) in water:EtOH solution (20 ml,3:1). The resulting mixture was then set to heat at 50° C. for 1 hour.The reaction was allowed to cool to room temperature and partitionedwith EtOAc. The layers were cut and the organic layer was then driedover Na₂SO₄, filtered and concentrated in vacuo. The crude residueobtained was then purified by silica gel chromatography (Biotage HorizonSystem) using a gradient elution of 5-50% EtOAc in DCM to give 815 mg ofthe title compound (60% overall yield, 2 steps). ¹H NMR: 11.22 (s, 1H)9.75 (s, 1H) 8.22 (dd, J=7.54, 1.88 Hz, 1H) 7.30-7.46 (m, 1H) 7.24 (dd,J=10.93, 8.67 Hz, 1H) 1.98-2.18 (m, 6H).

Method 68

N-(5-Acetyl-2-fluorophenyl)acetamide

To a round, bottom flask was added 3-amino-4-fluoroacetophenone (Method64, 1 g, 6.54 mmol) in DMF (15 ml), followed by the addition of acetylchloride (0.56 ml, 7.84 mmol) and DIEA (2.3 ml, 13.08 mmol). Thesolution was set to stir at room temperature. The reaction appearedcomplete by TLC after 30 min. The reaction was then quenched with waterand partitioned with EtOAc. The layers were cut, followed by anadditional wash of the aqueous with EtOAc. The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue obtained (1.17 g), was used directly in the next step. ¹H NMR(CDCl₃) δ 8.94 (d, J=7.54 Hz, 1H) 7.71 (d, 1H) 7.43 (s, 1H) 7.15 (s, 1H)2.56-2.60 (m, 3H) 2.21-2.28 (m, 3H).

Method 69

N-[5-(1-Aminoethyl)-2-fluorophenyl]cyclopropanecarboxamide

To a round, bottom flask was addedN-{2-fluoro-5-[(1Z)-N-hydroxyethanimidoyl]phenyl}cyclopropanecarboxamide(Method 70, 458 mg, 1.94 mmol) and HOAc (1 ml) in EtOH (25 ml), followedby the addition of Palladium on carbon (100 mg, 10 wt %) under N₂atmosphere. Once the catalyst was added, the system was evacuated andpurged with hydrogen (atmospheric pressure). This process was performedseveral times to ensure complete saturation of hydrogen to the system.The reaction was then allowed to stir for 16 hours at room temperature.The heterogenous mixture was then filtered over a pad of celite and thefiltrate was concentrated in vacuo to give quantitative yield of thetitle compound. ¹H NMR: 9.99 (s, 1H) 7.85 (d, J=8.29 Hz, 1H) 7.17 (s,J=8.29 Hz, 2H) 4.03 (d, J=6.03 Hz, 1H) 1.90-2.04 (m, 1H) 1.26 (d, J=6.78Hz, 3H) 0.78 (d, J=6.03 Hz, 4H)

Method 70

N-{2-Fluoro-5-[(1Z)-N-hydroxyethanimidoyl]phenyl}cyclopropanecarboxamide

To a round, bottom flask was addedN-(5-acetyl-2-fluorophenyl)cyclopropanecarboxamide (Method 71, 458 mg,2.07 mmol), hydroxyl amine hydrochloride salt (288 mg, 4.14 mmol), andNaOAc (424 mg, 5.17 mmol) in water-EtOH solution (7 ml, 3:1). Thereaction mixture was set to heat at 50° C. for 1 hour. As the reactionreached desired temperature, no dissolution was observed, thus more EtOH(7 ml) was added for dissolution to occur. The reaction was completeafter 1 hour and concentrated in vacuo. The title compound (458 mg, 94%yield) was used directly in next step. ¹H NMR: 11.32 (s, 1H) 10.10 (s,1H) 8.19 (d, J=6.03 Hz, 1H) 7.30-7.44 (m, 1H) 7.23 (s, 1H) 2.09 (s, 3H)2.01 (s, 1H) 0.79 (s, 4H).

Method 71

N-(5-Acetyl-2-fluorophenyl)cyclopropanecarboxamide

To a round, bottom flask was added 3-amino-4-fluoroacetophenone (Method64, 1 g, 6.54 mmol), cyclopropyl carboxylic acid (0.62 ml, 7.84 mmol),HATu (2.5 g (6.57 mmol), and DIEA (2.3 ml, 13.08 mmol) in DMF (15 ml).The reaction mixture was allowed to stir at room temperature for 16hours. The reaction mixture was quenched with water and partitioned withEtOAc. The layers were cut, followed by an additional wash of theaqueous with EtOAc. The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo. The crude residue obtained was thenpurified by silica gel chromatography (Biotage Horizon System) using agradient elution of 5-15% EtOAc in DCM to give 458 mg of the titlecompound (32% isolated yield). ¹H NMR: 10.16 (s, 1H) 8.53 (dd, J=7.91,2.26 Hz, 1H) 7.67-7.82 (m, 1H) 7.40 (dd, J=10.55, 8.67 Hz, 1H) 2.54 (s,3H) 1.95-2.09 (m, 1H) 0.78-0.88 (m, 4H).

Method 72

1-(5-Fluoro-pyrimidin-2-yl)ethanamine

A round-bottom flask containing 2-(1-azidoethyl)-5-fluoropyrimidine(Method 73, 0.60 g, 3.59 mmol) was charged with 10% Pd/C (0.191 g) andwas evacuated and backfilled with H₂ via a filled balloon. MeOH (10 ml)was added, and the mixture was allowed to stir at room temperature for 3hours. The mixture was filtered through a plug of diatomaceous earth,which was subsequently washed well with MeOH. The filtrates wereconcentrated to give the title compound as a pale yellow oil (0.50 g,99%). ¹H NMR (CDCl₃) δ 8.60 (s, 2H), 4.65 (br s 2H), 4.10 (m, 1H), 1.20(d, 3H).

Method 73

2-(1-Azidoethyl)-5-fluoropyrimidine

A round-bottom flask containing 1-(5-fluoropyrimidin-2-yl)ethanol(Method 74, 0.79 g, 5.55 mmol) was charged with triethylamine (0.67 g,6.66 mmol) and anhydrous DCM (10 ml). The solution was cooled to 0° C.,and methanesulfonyl chloride (0.70 g, 4.1 mmol) was added dropwise. Theresulting mixture was allowed to stir at room temperature for 2 hours,at which point the volatile components were removed using a rotaryevaporator. The residue was dissolved in DMF (15 ml) and treated withsodium azide (0.72 g, 11.1 mmol). The resulting mixture was stirred atroom temperature for 60 hours. It was then partitioned between EtOAc andbrine. The organic layer was obtained, dried (Na₂SO₄), and evaporated todryness. The crude material was purified by silica gel chromatography(by ISCO Combiflash with gradient EtOAc and hexanes) to afford the titlecompound as a colourless oil (0.60 g, 65% yield over two steps). GC-MS,167 (M), 138 (M-N₂), 125 (M-N₃); ¹H NMR (CDCl₃) δ 8.60 (s, 2H), 4.60 (m,1H), 1.65 (d, 3H).

Method 74

1-(5-Fluoropyrimidin-2-yl)ethanol

1-(5-Fluoropyrimidin-2-yl)ethanone (Method 75, 0.77 g) was dissolved inMeOH (15 ml), and the solution was cooled to 0° C. NaBH₄ (0.210 g, 5.55mmol) was added. The mixture was stirred at room temperature for 1 hourand then partitioned between EtOAc and H₂O. The organic extract waswashed with brine, dried (Na₂SO₄), filtered, and concentrated to givethe title compound as a yellowish oil (0.79 g, 99%). ¹H NMR (CDCl₃) δ8.65 (s, 2H), 5.20 (m, 1H), 4.00 (br s, 1H), 1.80 (d, 3H).

Method 75

1-(5-Fluoropyrimidin-2-yl)ethanone

A round-bottom-flask containing 5-fluoropyrimidine-2-carbonitrile(Method 59, 1.50 g, 12.19 mmol) was charged with anhydrous THF (30 ml)under N₂. The solution was cooled to 0° C., and a solution of MeMgBr(4.90 ml of a 3.0 M solution in ether, 14.62 mmol) was added dropwise.After 2 hours at 0° C., the reaction mixture was quenched with ice waterand extracted with EtOAc. The organic extract was washed with brine,dried over Na₂SO₄, and evaporated to dryness to give the title compoundas an oil (0.778 g, yield 46%). GC-MS, 140 (M); ¹H NMR (CDCl₃) δ 8.65(s, 2H), 2.65 (s, 2H).

Method 76

1-(6-Fluoro-pyridin-3-yl)ethanamine

To a slurry of Raney Nickel in EtOH solution (75 ml), under inertatmosphere, was added 1-(6-fluoropyridin-3-yl)ethanone oxime (Method 77,2.3 g, 14.9 mmol). The system was purged with hydrogen and evacuatedseveral times to ensure complete saturation with hydrogen. The reaction,after 2 hours stirring at room temperature, was filtered over celite andfiltrate collected was concentrated in vacuo to give 2 g (95% isolatedyield) of the title compound. ¹H NMR: 8.16 (s, 1H) 7.97 (t, J=8.29 Hz,1H) 7.09 (dd, J=8.29, 3.01 Hz, 1H) 4.03 (q, J=6.78 Hz, 1H) 1.23 (d,J=6.03 Hz, 3H).

Method 77

1-(6-Fluoropyridin-3-yl)ethanone oxime

To a 200-ml, round bottom flask was added,1-(6-fluoropyridin-3-yl)ethanone (Method 65, 2.5 g, 17.9 mmol),hydroxylamine hydrochloride (2.5 g, 35.8 mmol), and NaOAc (3.7 g, 44.8mmol) in a solution of water-EtOH (65 ml, 3.3:1). The resulting mixturewas heated to 50° C. for 1 hour. The reaction was then allowed to coolto room temperature, partitioned with EtOAc, layers were cut, andorganic layer was dried over Na₂SO₄, filtered, and concentrated in vacuoto afford the title compound in quantitative yield. ¹H NMR: 11.49 (s,1H) 8.47 (s, 1H) 8.17-8.27 (m, 1H) 7.21 (dd, J=8.29, 3.01 Hz, 1H) 2.17(s, 3H).

Method 78

tert-Butyl 5-amino-3-isopropoxy-1H-pyrazole-1-carboxylate

A solution of 5-isopropoxy-1H-pyrazol-3-amine (3.5 g, 24.8 mmol) in DCM(100 ml) was prepared at room temperature. A 4.5M aqueous KOH solution(11.1 g, 198 mmol) was added dropwise, followed by the addition ofdi-tert-butyl dicarbonate (5.68 g, 26 mmol) in DCM (20 ml). Theresulting reaction was then stirred vigorously for 30 hours, at whichpoint water (200 ml) was added and the layers were allowed to separate.The organic fraction was separated, dried (Na₂SO₄), filtered, and thenconcentrated. The resulting oil was purified by column chromatography(100:1 DCM:MeOH) to give the title compound (5.4 g, 90%). MS: Calcd.:241. Found: [M+H]⁺ 242.

Method 79

tert-Butyl5-(5-cyano-3,6-difluoropyridin-2-ylamino)-3-isopropoxy-1H-pyrazole-1-carboxylate

A solution of tert-butyl 5-amino-3-isopropoxy-1H-pyrazole-1-carboxylate(Method 78, 4.0 g, 16.4 mmol) in THF (45 ml) was cooled to −78° C. A1.0M THF solution of LiHMDS (2.61 g, 15.6 mmol) was added dropwise andthe reaction was stirred at −78° C. for 30 minutes. A −78° C. solutionof 2,5,6-trifluoronicotinonitrile (1.3 g, 8.2 mmol) in THF (20 ml) wasadded dropwise via cannula to the above anion solution. Upon completionof the addition, the resulting reaction was allowed to stir for 10minutes at −78° C., and was then quenched with water (100 ml). Thereaction was allowed to warm to room temperature, extracted with DCM(3×100 ml), dried (Na₂SO₄), filtered, and then concentrated to give thetitle compound (95% conversion by LCMS) which was used without furtherpurification. MS: Calcd.: 379. Found: [M+H]⁺ 380.

Utility

The compounds of the present invention have utility for the treatment ofcancer by inhibiting the tyrosine kinases, particularly the Trks andmore particularly Trk A and B. Methods of treatment target tyrosinekinase activity, particularly the Trk activity and more particularly TrkA and B activity, which is involved in a variety of cancer relatedprocesses. Thus, inhibitors of tyrosine kinase, particularly the Trksand more particularly Trk A and B, are expected to be active againstneoplastic disease such as carcinoma of the breast, ovary, lung, colon,prostate or other tissues, as well as leukemias and lymphomas, tumoursof the central and peripheral nervous system, and other tumour typessuch as melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinaseinhibitors, particularly the Trk inhibitors and more particularly Trk Aand B inhibitors are also expected to be useful for the treatment otherproliferative diseases including but not limited to autoimmune,inflammatory, neurological, and cardiovascular diseases.

In addition, the compounds of the invention are expected to be of valuein the treatment or prophylaxis of cancers selected with up regulated ofconstitutively activated Trk kinases, including but not limited to,oncogenic rearrangements leading to ETV6-TrkC fusions, TRP-TrkA fusionsproteins, AML-ETO (t8; 21), autocrine or paracrine signalling leading toelevated serum levels of NGF, BDNF, neurotropins or tumours withconstitutively active Trk associated with disease aggressiveness, tumourgrowth and proliferation or survival signalling.

Compounds of the present invention have been shown to inhibit tyrosinekinases, particularly the Trks and more particularly Trk A and B, asdetermined by the Trk A Assay described herein.

Compounds provided by this invention should also be useful as standardsand reagents in determining the ability of a potential pharmaceutical toinhibit tyrosine kinases, particularly the Trks and more particularlyTrk A and B. These would be provided in commercial kits comprising acompound of this invention

Trk A Assay Format

Trk A kinase activity was measured for its ability to phosphorylatesynthetic tyrosine residues within a generic polypeptide substrate usingan Amplified Luminescent Proximity Assay (Alphascreen) technology(PerkinElmer, 549 Albany Street, Boston, Mass.).

To measure Trk A kinase activity, the intracellular domain of aHIS-tagged human Trk A kinase (amino acids 442-796 of Trk A, Swiss-ProtPrimary Accession Number P04629) was expressed in SF9 cells and purifiedusing standard nickel column chromatography. After incubation of thekinase with a biotinylated substrate and adenosine triphosphate (ATP)for 20 minutes at room temperature, the kinase reaction was stopped bythe addition of 30 mM ethylenediaminetetraacetic acid (EDTA). Thereaction was performed in 384 well microtitre plates and the reactionproducts were detected with the addition of strepavidin coated DonorBeads and phosphotyrosine-specific antibodies coated Acceptor Beadsusing the EnVision Multilabel Plate Reader after an overnight incubationat room temperature.

Peptide substrate PolyEY-biotin (PGT-bio.) ATP Km 70 μM Assay conditions0.838 ng/ml Trk A, 9 mM HEPES, 45 μg/ml BSA, 10 mM MnCl₂, 5 nM PGT-bio,0.01% Triton ® X-100, 70 μM ATP Incubation 20 minutes, room temperatureTermination/Detection 6.3 mM HEPES, 30 mM EDTA, 525 μg/ml BSA,conditions 40 mM NaCl, 0.007% Triton ® X-100, 12 ng/ml of Donor Beads,12 ng/ml of Acceptor Beads Detection incubation overnight, roomtemperature Fluometer settings Excitation = 680 nM Emission = 570 nMExcitation Time = 180 ms Total Measurement Time = 550 ms

Although the pharmacological properties of the compounds of the formula(I) vary with structural change, in general activity possessed bycompounds of the formula (I) may be demonstrated at IC₅₀ concentrations(concentrations to achieve 50% inhibition) or doses in the range of(0.01 μM to 10 μM).

When tested in the above in-vitro assay the Trk inhibitory activity ofthe following examples was measured at the following IC₅₀s.

Ex IC₅₀ (μM) 21 0.611 24 0.109 47 0.063

1.(S)-5-Fluoro-2-(1-(5-fluoropyridin-2-yl)ethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile,or a pharmaceutically acceptable salt thereof.
 2. A method of inhibitingTrk activity comprising administering to a host in need of suchtreatment a therapeutically effective amount of(S)-5-fluoro-2-(1-(5-fluoropyridin-2-yl)ethylamino)-6-(5-isopropoxylH-pyrazol-3-ylamino)nicotinonitrile,or a pharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition comprising(S)-5-fluoro-2-(1-(5-fluoropyridin-2-yl)ethylamino)-6-(5-isopropoxylH-pyrazol-3-ylamino)nicotinonitrile,or a pharmaceutically acceptable salt thereof, together with at leastone pharmaceutically acceptable carrier, diluent or excipient.